JP2019123757A - Compositions and methods for transmucosal absorption - Google Patents

Abstract

To provide improved compositions and methods for administering a therapeutic compound for wound-healing, in particular, cyclobenzaprine or amitriptyline for transmucosal absorption, where the compositions further comprise a basifying agent as well as the therapeutic agent.SOLUTION: The composition and method of the invention have a number of surprising pharmacokinetic benefits over oral administration. The invention also provides a method for treating fibromyalgia in a human subject. In some embodiments, the invention provides a composition comprising cyclobenzaprine suitable for transmucosal absorption. In some embodiments, the invention provides a composition suitable for transmembrane absorption comprising cyclobenzaprine and a basifying agent.SELECTED DRAWING: None

Description

Cross Reference to Other Applications This application is based on US Provisional Patent Application No. 61 / 660,593 filed on Jun. 15, 2012, US Provisional Patent Application No. 61/667, filed on July 3, 2012. No. 774, U.S. Provisional Patent Application No. 61 / 725,402, filed November 12, 2012, and U.S. Provisional Patent Application No. 61 / 792,900, filed March 15, 2013 Claim priority. The disclosures of these applications are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Cyclobenzaprine, or 3- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -N, N-dimethyl-1-propanamine, initially for treating acute muscle spasms of local origin It was approved by the US Food and Drug Administration in 1977. (Katz, W. et al., Clinical Therapeutics 10: 216-228 (1988)). Amitriptyline, or 3- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-ylidene) -N, N-dimethyl-1-propanamine, is initially an American food to treat depression Approved by the medical department.
Subsequent studies have also shown that cyclobenzaprine is effective in treating fibromyalgia syndrome, post traumatic stress disorder (PTSD), traumatic brain injury (TBI), generalized anxiety disorder and depression. Furthermore, the utility of cyclobenzaprine as a drug to improve sleep quality, as a drug to deepen sleep, or to treat sleep disturbance has been investigated. However, while FDA-approved treatments address pain and mood, there are currently no FDA-approved treatments that address sleep disturbance and fatigue associated with fibromyalgia syndrome. Treatment with cyclobenzaprine is particularly fibromyalgia syndrome, long-term fatigue, chronic fatigue, chronic fatigue syndrome, sleep disorder, psychogenic pain disorder, chronic pain syndrome (type II), drug administration, autoimmune disease, stress Or it may be useful to treat sleep disturbances caused or exacerbated or associated with anxiety or treating or symptoms of sleep disorders caused or exacerbated by sleep disturbances. See, eg, US Pat. Nos. 6,395,788 and 6,358,944, which are incorporated herein by reference.
Although cyclobenzaprine has broad therapeutic utility, cyclobenzaprine is slowly absorbed into the bloodstream after oral administration, so it should be taken approximately 1-2 hours before the effect is sought. is there. Even if the effect is sought more rapidly, the patient must wait for the effect to occur, which is undesirable for use as a sleep aid and has symptoms of muscle spasm seeking relief. Not desirable for the patient. In part, oral cyclobenzaprine is so slow acting that patients with cramped fibromyalgia are not effective in treating sleep quality problems associated with fibromyalgia, The use of prescription sedatives or sleeping aids that may become sexual may seek to manage non-restoring sleep associated with fibromyalgia. Despite the broad therapeutic utility of cyclobenzaprine, cyclobenzaprine often causes fatigue, somnolence, aching sensation, or cognitive impairment in individuals, which is a state of alertness Not desirable during normal periods. Cyclobenzaprine is also recommended for short-term use only, as it has not been shown to benefit during long-term dosing. In part, because cyclobenzaprine is not used in long-term treatment, cramped fibromyalgia patients are not effective in treating fibromyalgia pain and may become addictive opiate analgesia Agents may be used to manage the pain associated with fibromyalgia. Studies with various formulations of cyclobenzaprine have shown that absorption of cyclobenzaprine after oral administration is slow and that delaying is designed to target the sleeping brain with a once-daily treatment It has been concluded that this leads to undesirable characteristics for bedtime medications. Thus, improved cyclobenzaprine formulations are desirable.

U.S. Patent No. 6,395,788 U.S. Patent No. 6,358,944

SUMMARY OF THE INVENTION In some embodiments, the present invention provides a composition comprising cyclobenzaprine suitable for transmucosal absorption. In some embodiments, the present invention provides a composition comprising cyclobenzaprine and a basifying agent that is suitable for transmucosal absorption.

  In some embodiments, the present invention provides a composition comprising amitriptyline, which is suitable for transmucosal absorption. In some embodiments, the present invention provides a composition comprising amitriptyline and a basifying agent, which is suitable for transmucosal absorption.

  In certain embodiments, the basifying agent is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, phosphoric acid It is selected from the group consisting of sodium dihydrogen, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate and trisodium citrate.

  In certain embodiments, transmucosal absorption is oral absorption. In certain embodiments, the composition is suitable for sublingual administration. In a further embodiment, the composition is in the form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.

  In certain embodiments, the composition is suitable for buccal administration. In a further embodiment, the composition is in a form selected from the group consisting of an oral tablet, a lozenge, an oral tablet, and an oral spray solution.

  In certain embodiments, transmucosal absorption is intranasal absorption. In a further embodiment, the composition is in the form of a nasal spray solution. In certain embodiments, transmucosal absorption is transpulmonary absorption. In a further embodiment, the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.

In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 50 ± 25% × 10 ⁻⁹ mL ⁻¹ or more 10 minutes after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 125 ± 25% × 10 ⁻⁹ mL ⁻¹ or greater at 15 minutes after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 150 ± 25% × 10 ⁻⁹ mL ⁻¹ or more 20 minutes after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or more 30 minutes after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 450 ± 25% × 10 ⁻⁹ mL ⁻¹ or more at 45 minutes after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a DNC ^* of 600 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 1 hour of administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or more two hours after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is 750 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 2.5 hours (150 minutes) of administration. It is characterized by having dnC ^* . In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^{* of} at least 850 ± 25% × 10 ⁻⁹ mL ⁻¹ three hours after administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 900 ± 25% × 10 ⁻⁹ mL ⁻¹ after 3.3 hours (200 minutes) of administration. It is characterized by having dnC ^* . In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 950 ± 25% × 10 ⁻⁹ mL ⁻¹ after 3.7 hours (220 minutes) of administration. It is characterized by having dnC ^* . In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a DNC ^* of 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 4 hours of administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ after 4.33 hours (260 minutes) of administration. It is characterized by having dnC ^* . In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is more than 1050 ± 25% × 10 ⁻⁹ mL ⁻¹ after 4.67 hours (280 minutes) of administration. It is characterized by having dnC ^* . In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 5 hours of administration. It is characterized by In some embodiments, the composition, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline, 5.5 hours after ^{1000 ± 25% × 10 -9 mL} -1 or more DNC ^* administration It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC ^* of 900 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 6 hours of administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or more at 8 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of less than or equal to 650 ± 25% × 10 ⁻⁹ mL ⁻¹ at 10 hours post administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of less than or equal to 500 ± 25% × 10 ⁻⁹ mL ⁻¹ 12 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of less than or equal to 500 ± 25% × 10 ⁻⁹ mL ⁻¹ 14 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 350 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 16 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 350 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 18 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 20 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 22 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 24 hours of administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 200 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 36 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 150 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 48 hours after administration. It is characterized by In some embodiments, when administered via transmucosal absorption, the cyclobenzaprine or amitriptyline has a dnC ^* of 100 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 72 hours of administration. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline at least 2.0 ± 25% × 10 ⁻⁹ mL ⁻¹ or more dnC ^* at 30 minutes after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline at least 2.0 ± 25% x 10 ^-9 mL ^-1 or more dnC ^* at 45 minutes after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline at least 2.0 ± 25% × 10 ⁻⁹ mL ⁻¹ dnC ^* at 1 hour post administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline at least 2.0 ± 25% × 10 ⁻⁹ mL ⁻¹ dnC ^* at 2 hours post administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline at least 2.0 ± 25% × 10 ⁻⁹ mL ⁻¹ dnC ^* three hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* 8 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* at 10 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* 12 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* 14 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* 16 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* at 18 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* at 20 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* at 22 hours after administration. It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline does not exceed 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ dnC ^* 24 hours after administration. It is characterized by having.

In some embodiments, the composition has cyclobenzaprine or _{amitryptiline} , when administered by transmucosal absorption, having a dnAUC _0-8h greater than or _equal to 5 ± 25% × 10 ⁻⁶ mL ⁻¹ · hr. It features. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnAUC _0-∞h of 20 ± 25% × 10 ⁻⁶ mL ⁻¹ · hr or more. It is characterized by In some embodiments, the composition is characterized in that when administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dnC _max ^* of 1.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more. I assume. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a partial AUC _{0-20 min} , 128 ± 25 of 37 ± 25% ng · hr · L ⁻¹ or higher. % ng · hr · ^{L -1} or more _{AUC 0-30min, 333 ± 25% ng} · hr · L -1 or more _{AUC 0-45min, 614 ± 25% ng} · hr · L -1 or more _{AUC 0-1H} , 2098 ± 25% ng · hr · L -1 or more _{AUC 0-2h, 2955 ± 25% ng} · hr · L -1 or more _{AUC 0-2.5h, 3931 ± 25% ng} · hr · L -1 It is characterized by having the above AUC _0-3h . In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a partial AUC _{0-20 min} , 86 ± 25 of 23 ± 25% ng · hr · L ⁻¹ or higher. % ng · hr · ^{L -1} or more _{AUC 0-30min, 223 ± 25% ng} · hr · L -1 or more _{AUC 0-45min, 405 ± 25% ng} · hr · L -1 or more _{AUC 0-1H} , and having a 1478 ± 25% ng · hr · L -1 or more _{AUC 0-2h, 2167 ± 25% ng} · hr · L -1 or more _{AUC 0-2.5h.} In some embodiments, dnAUC 0-20 _min is about 0.02 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ and dnAUC _{0-30 min} is about 0.05 ± 25% × 10 ⁻⁶ hr · ML ^-1 , dnAUC 0-45 _min is about 0.15 ± 25% × 10 ^-6 hr · mL ^-1 , dnAUC _{0-1 h} is about 0.25 ± 25% × 10 ^-6 hr · ^mL is ^{_-1, dnAUC 0-2h} is about ^{0.9 ± 25% × 10 -6 hr} · mL -1, dnAUC 0-2.5h is about 1.2 ± 25% × 10 ^{- 6} hr · mL ⁻¹ , dnAUC 0-3 _h is about 1.5 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _{3.3 h} is about 1.8 ± 25% × 10 ^{− 6} hr · mL ⁻¹ , and dnAUC _{0-3.7 h} is approximately 2.3 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , dnAUC _0−4h is approximately 2.6 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _0−4.3h is approximately 3.0 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , dnAUC 0−4.7 _h is approximately 3.3 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _{0-5 h} is approximately 3. 7 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , dnAUC _{0−5.5 h} is about 4.2 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _{0-6 h} is about 4.7 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , dnAUC _0-8h is 6.30 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _0-12h is approximately 20 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , and dnAUC _0-−h is approximately 25 ± 25% × 10 ⁻⁶ hr -It is mL- ¹ .

In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 1.0 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _{0-20 min} It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 3.5 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _{0-30 min} It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _{0-45 min} of 10 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _{0-1 h} of 18 ± 25% × 10 ⁻⁶ kg · hr ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _0-2h of 60 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 85 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _0-2.5h It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _{0-3h of} at least 115 ± 25% × 10 ⁻⁶ kg · hr ^−1. It is characterized by In some embodiments, the composition has cyclobenzaprine or amitriptyline, when administered by transmucosal absorption, having a dbmnAUC _3.3h greater than or _equal to 135 ± 25% × 10 ⁻⁶ kg · hr ^−1. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 160 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _{0-3.7 h} It is characterized by having. In some embodiments, the composition has cyclobenzaprine or amitriptyline, when administered by transmucosal absorption, having a dbmnAUC _0-4h of 180 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 210 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _{0-4.3 h} It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 230 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _0-4.7h It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _0-5h of 250 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline is greater than or equal to 290 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC ₀ −5.5 _h It is characterized by having. In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _0-6h of 330 ± 25% × 10 ⁻⁶ kg · hr ⁻¹ or more. It is characterized by In some embodiments, the composition has cyclobenzaprine or amitriptyline having a 440 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ dbmnAUC _0-8h when administered by transmucosal absorption It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC _{0-12 h} of 1500 ± 25% × 10 ⁻⁶ kg · hr ⁻¹ or more. It is characterized by In some embodiments, when the composition is administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a dbmnAUC ₀ -Inf of at least 1800 ± 25% × 10 ⁻⁶ kg · hr ^−1. It is characterized by

In some embodiments, the composition is characterized in that when administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a plasma concentration of 50% or less of C _max 8 hours after administration. In some embodiments, the composition is characterized in that, when administered by transmucosal absorption, cyclobenzaprine or amitriptyline has a plasma concentration of 50% or less of C _max 12 hours after administration.

  In some embodiments, cyclobenzaprine is present in the compositions of the invention in an amount of 0.1 mg to 10 mg, such as 0.1 mg to 5 mg. In certain embodiments, cyclobenzaprine is present in an amount of about 2.4 mg, less than about 2.4 mg, about 4.8 mg, or less than about 4.8 mg. In certain embodiments, cyclobenzaprine is present in an amount of about 2.8 mg, less than about 2.8 mg, about 5.6 mg, or less than about 5.6 mg. In certain embodiments, cyclobenzaprine is present in an amount of less than about 4.5 mg, less than about 5 mg, about 9 mg, or about 10 mg.

In some embodiments, the composition is characterized in that it produces a _Cmax of cyclobenzaprine of 10 ng / mL or more when administered by transmucosal absorption. In some embodiments, the composition provides a _Cmax of cyclobenzaprine of at least 15 ng / mL, at least 20 ng / mL, at least 25 ng / mL, or at least 30 ng / mL when administered by transmucosal absorption. It features. In some embodiments, the composition provides a _Cmax of cyclobenzaprine of 2.5 ng / mL or more, 3 ng / mL or more, 4 ng / mL or more, 10 ng / mL or more when administered by transmucosal absorption It is characterized by In some embodiments, the composition is at least 2.74 ng / mL, at least 3.20 ng / mL, at least 5.13 ng / mL, or at least 10.27 ng / mL cyclobenza when administered by transmucosal absorption. It is characterized by bringing about C _max of pudding.

In some embodiments, the composition, when administered by transmucosal absorption, has a baseline level of cyclobenzaprine in the individual immediately prior to administration of at least 10 ng / mL, at least 15 ng / mL, at least 20 ng / mL, 25 ng / mL. It is characterized in that it results in a _Cmax of cyclobenzaprine of more than mL, or more than 30 ng / mL. In some embodiments directed to continuously repeated once-daily long-term administration, the composition comprises a baseline level of cyclobenzaprine in the individual immediately prior to administration of at least 10 ng / mL, when administered by transmucosal absorption. It is characterized in that it provides C _max of cyclobenzaprine which is 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, or 30 ng / mL or more. In some embodiments, the composition, when administered by transmucosal absorption, has a baseline level of cyclobenzaprine in the individual just prior to administration of 2.74 ng / ml or more, 3.20 ng / ml or more, 5.13 ng It is characterized in that it results in a C10 _max of cyclobenzaprine of more than 10 ml / ml or more than 10.27 ng / ml. In some embodiments relating to continuously repeated once-daily long-term administration, the composition comprises, when administered by transmucosal absorption, a baseline level of cyclobenzaprine in the individual just prior to administration of at least 10 ng / ml, It is characterized in that it results in C _max of cyclobenzaprine exceeding 15 ng / ml, 20 ng / ml, 25 ng / ml, or 30 ng / ml or more.

In some embodiments, the composition is characterized in that it provides a cyclobenzaprine t _max of less than 4.70 hours when administered by transmucosal absorption.

In some embodiments, the composition is at least 50%, at least 60%, at least 70%, at least 80% lower in C _{max by} 8 hours after administration when administered by transmucosal absorption. It is characterized in that it results in plasma levels of pudding.

  In some embodiments, the invention provides a method of treating a disease or condition in an individual in need thereof comprising administering a composition described herein by transmucosal absorption. An exemplary disease or condition is post-traumatic stress disorder (PTSD). In further embodiments, administration of the composition treats the onset of PTSD after a traumatic event, the onset of PTSD after a traumatic event, the intensification of PTSD after a traumatic event, or the persistence of PTSD after a traumatic event. In certain embodiments, the disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, muscle spasm, acute pain, and anxiety disorder Be done.

  In some embodiments, basifying agents useful in the methods of the present invention are potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate , TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, sodium acetate, tripotassium citrate, dipotassium citrate, trisodium citrate and trisodium citrate It is selected from the group consisting of disodium citrate.

  In some embodiments, oral absorption in the methods of the invention is sublingual absorption. In certain embodiments, the composition is in a form selected from the group consisting of a sublingual tablet, sublingual film, sublingual powder, and sublingual spray solution.

  In some embodiments, oral absorption in the methods of the invention is buccal absorption. In certain embodiments, the composition is selected from the group consisting of buccal tablets, lozenges, buccal tablets, and buccal spray solutions.

  In some embodiments, transmucosal absorption useful in the methods of the invention is intranasal absorption. In certain embodiments, the composition is in the form of a nasal spray solution.

  In some embodiments, transmucosal absorption useful in the methods of the present invention is transpulmonary absorption. In certain embodiments, the composition is in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.

In some embodiments, the present invention provides cyclobenzaprine or amitriptyline at 8.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or higher at 15 minutes after administration, and 1.0 ± 25% at 30 minutes after administration. 10 ^-6 mL ^-1 or more, 45 minutes after administration, 1.0 ± 25% × 10 ^-6 mL ^-1 or more, 1 hour after administration, 1.0 ± 25% × 10 ^-6 mL ^-1 or more, Methods are provided having dnC ^* of 1.0 x 25% x ^10-6 mL- ¹ or greater after 2 hours, or 1.0 x mL- ¹ or greater after 3 hours of dosing. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less at 8 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of less than or equal to 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ at 10 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitryptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less 12 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less 14 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less 16 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less 18 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less 20 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ or less at 22 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of less than or equal to 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ 24 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 50 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 10 minutes of administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 150 ± 25% × 10 ⁻⁹ mL ⁻¹ or more 20 minutes after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or more at 30 minutes after administration. In some embodiments, the present invention provides a method in which cyclobenzaprine or amitryptyline has a dnC ^* of 450 ± 25% × 10 ⁻⁹ mL ⁻¹ or more at 45 minutes after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 600 ± 25% × 10 ⁻⁹ mL ⁻¹ or more one hour after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or more two hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 750 ± 25% × 10 ⁻⁹ mL ⁻¹ or more at 2.5 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitryptiline has a dnC ^* of 850 ± 25% × 10 ⁻⁹ mL ⁻¹ or more three hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a 900 ± 25% × 10 ⁻⁹ mL ⁻¹ or more dnC ^* at 3.3 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of greater than or equal to 950 ± 25% × 10 ⁻⁹ mL ⁻¹ at 3.7 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 4 hours of administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of greater than 1050 ± 25% × 10 ⁻⁹ mL ⁻¹ 4.33 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of less than 1050 ± 25% × 10 ⁻⁹ mL ⁻¹ at 4.67 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitryptyline has a dnC ^* of 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 5 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitryptyline has a dnC ^* of less than or equal to 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ 5.5 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 900 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 6 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 8 hours after administration. In some embodiments, the present invention provides methods wherein cyclobenzaprine or amitriptyline has a dnC ^* of 500 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 12 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 350 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 16 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 24 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 180 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 36 hours after administration. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC ^* of 140 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 48 hours after administration. In some embodiments, the present invention provides methods wherein cyclobenzaprine or amitriptyline has a dnC ^* of 90 ± 25% × 10 ⁻⁹ mL ⁻¹ or less at 72 hours after administration.

In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnAUC _0-8h of 5 mL- ¹ · hr or more. In some embodiments, cyclobenzaprine or amitriptyline has a dNAUCo _-∞h of 20 mL- ¹ · hr or more. In some embodiments, the present invention provides methods in which cyclobenzaprine or amitriptyline has a dnC _max ^* of 1.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more. In some embodiments, the present invention provides a method in which cyclobenzaprine or amitriptyline has a dNACO- _8h of 6.3 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ or more. In some embodiments, cyclobenzaprine or amitriptyline has a dnAUC _0-∞ h of 25 ± 25% × 10 ⁻⁶ hr mL ⁻¹ or higher. In some embodiments, the present invention is, cyclobenzaprine or amitriptyline, provides a method with ^{1.1 ± 25% × 10 -6 mL} -1 or more _{DNC max} ^*.

In some embodiments, the present invention is, cyclobenzaprine or amitriptyline, less than 50% of the _{C max} after 4 hours of administration, less than 50% of the _{C max} after 6 hours of administration, the _{C max} after 8 hours of administration Provided are methods having a plasma concentration of 50% or less, or 50% or less of C _max 12 hours after administration.

  In some embodiments, the present invention provides a method wherein cyclobenzaprine is present in the composition in an amount of 0.1 mg to 10 mg. In certain embodiments, cyclobenzaprine is in the composition in an amount of 0.1 mg to 5 mg, such as an amount of about 2.4 mg, an amount of less than about 2.4 mg, an amount of about 4.8 mg, or about 4 Less than .8 mg, or less than about 2.8 mg, less than about 5.6 mg, or less than about 5.6 mg, less than about 9.0 mg, less than about 10 mg Exists in

In some embodiments, the present invention provides that the composition is 10 ng / mL or more, 15 ng / mL or more, 20 ng / mL or more, 25 ng / mL or more, 30 ng / mL or more, 40 ng / mL or more, 50 ng / mL or more, 60 ng / mL or more, 70 ng / mL or more, 80 ng / mL or more, 90 ng / mL or more, 100 ng / mL or more, 120 ng / mL or more, 140 ng / mL or more, 150 ng / mL or more, 160 ng / mL or more, 170 ng / mL or more, Provided are methods that result in a _Cmax of cyclobenzaprine of 180 ng / mL or more, 190 ng / mL or more, 200 ng / mL or more, 220 ng / mL or more, 240 ng / mL or more, 260 ng / mL or more, or 280 ng / mL or more. In some embodiments, the present invention provides that the composition is at least 2.74 ng / ml, at least 3.20 ng / ml, at least 5.13 ng / ml, at least 10.27 ng / ml, at least 2 ng / ml, at least 3 ng / ml. Provided is a method of providing _Cmax of cyclobenzaprine greater than or equal to ml.

In some embodiments, the present invention provides that the composition is 10 ng / mL or more above the baseline level of cyclobenzaprine in the individual just prior to administration, 20 ng / mL or more above the baseline level, 20 ng / mL or more. More than mL, more than 25 ng / mL more than baseline level, more than 30 ng / mL more than baseline level, more than 40 ng / mL more than baseline level, more than 50 ng / mL more than baseline level, 60 ng / mL of baseline level More than mL, more than 70 ng / mL above baseline level, more than 80 ng / mL more than baseline level, more than 90 ng / mL above baseline level, more than 100 ng / mL more than baseline level, 120 more than baseline level More than g / mL, more than 140 ng / mL above baseline level, more than 150 ng / mL above baseline level, more than 160 ng / mL above baseline level, more than 170 ng / mL above baseline level, above baseline level More than 180 ng / mL, more than 190 ng / mL above baseline level, more than 200 ng / mL more than baseline level, more than 220 ng / mL above baseline level, more than 240 ng / mL more than baseline level, above baseline level Provided is a method that results in a cyclobenzaprine C _max of greater than or equal to 260 ng / mL, or greater than or equal to 280 ng / mL or above baseline levels. In some embodiments pertaining to continuously repeated once-daily long-term administration, the present invention provides that the composition is at least 10 ng / mL above baseline levels of cyclobenzaprine in the individual just prior to administration. More than 15 ng / mL, more than 20 ng / mL above baseline level, more than 25 ng / mL more than baseline level, more than 30 ng / mL above baseline level, more than 40 ng / mL more than baseline level, above baseline level More than 50 ng / mL, more than 60 ng / mL above baseline level, more than 70 ng / mL more than baseline level, more than 80 ng / mL above baseline level, more than 90 ng / mL more than baseline level 100 ng / mL Above baseline, above baseline level by 120 ng / mL or above, above baseline level by 140 ng / mL or above, above baseline level by 150 ng / mL or above, above baseline level by 160 ng / mL or above, baseline level 170 ng / mL More than baseline level more than 180 ng / mL more than baseline level more than 190 ng / mL more than baseline level more than 200 ng / mL more than baseline level more than 220 ng / mL more than baseline level 240 ng / mL Provided is a method that results in a cyclobenzaprine C _max of greater than baseline levels by 260 ng / mL or more, or 280 ng / mL or more of baseline levels. In some embodiments, the present invention provides that the composition exceeds baseline levels by 2.74 ng / ml or more, baseline levels by 3.20 ng / ml or more, baseline levels by 5.13 ng / ml or more , 10.27 ng / ml or more above baseline level, 2 ng / ml or more above baseline level, 3 ng / ml or more above baseline level, 10 ng / ml or more above baseline level, 15 ng / ml or more above baseline level Provided that the C _max of cyclobenzaprine is greater than 20 ng / ml or more, 25 ng / ml or more above the baseline level, 30 ng / ml or more above the baseline level, or 40 ng / ml or more above the baseline level.

In some embodiments, the present invention provides that the composition is less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 10 minutes, or 5 minutes Provide a method that results in a cyclobenzaprine t _max of less.

In some embodiments, the present invention provides a composition is at least 50% of C _max by 8 hours after administration, at least 60% of the C _max by 8 hours after administration, up to 8 hours after administration at least 70% of C _max, at least 80% of the _{C max} by 8 hours after administration, at least 90% of _{C max} by 8 hours after administration, or at least 95% of the _{C max} by 8 hours after administration Methods are provided that result in reduced plasma levels of cyclobenzaprine.

In some embodiments, the present invention is a composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation comprises about 0. Providing a _Cmax of about 20 to about 200 ng / mL cyclobenzaprine after about 05 to about 2.5 hours, and a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL about 22 to about 26 hours after administration A composition is provided that is administered once or more daily for 4 days or more. In some embodiments, the present invention is a composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation comprises resulting in _{C max,} and the minimum plasma concentration of from about 1 to about 5 ng / ml to about 22 to about 26 hours after administration of about 5.0 hours after about 1.0 ng / ml to about 30.0ng / ml of cyclobenzaprine , Provided once daily for 4 days or more and administered within 2 hours prior to sleep.

In some embodiments, the present invention is a composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation comprises After about 26 hours, dnC _{min (24)} ^* of cyclobenzaprine of about 100 ± 25% × 10 ⁻⁹ mL ⁻¹ to about 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ is obtained, and the composition A composition is provided that is administered for 4 or more days in a single dose and is administered within 2 hours prior to sleep. In some embodiments, the present invention is a composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein the formulation is for 24 hours after administration Or give a dnC _{min (24)} ^* of cyclobenzaprine of 300 ± 25% x 10 ^-9 mL ^-1 or less after 22 to about 26 hours ₍ use an average C _{min (24)} 706.55pg / mL after 24 hours DnC _{min (24)} ^* is calculated as ((706.55 pg / mL) / (2.4 mg)) = 294.40 pg / (mg · mL), or 300 ± 25% × 10 ⁻⁹ mL ^{− 1} ), the composition is administered once daily for 4 days or more and provides a composition administered within 2 hours before sleep.

In some embodiments, the present invention is a method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof. Said formulation comprises a _Cmax of about 20 to about 200 ng / mL of cyclobenzaprine at about 0.05 to about 2.5 hours after administration, and about 1 to about 5 ng / hour after about 22 to about 26 hours of administration. This results in a minimum plasma concentration in mL and provides a method wherein the composition is administered in a single daily dose for 4 or more days and is administered within 2 hours before sleep.

In some embodiments, the present invention is a method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2.4 mg of cyclobenzaprine or a salt thereof. , wherein the preparation is in the single dose study, approximately _{C max} of 4.70 hours after about 2.74μg · ^{mL -1} of cyclobenzaprine, and after about 24 hours at about 706.55ng · ^mL dose administration ^-1 Provides a method wherein the composition is administered in one or more daily doses for four or more days and is administered within two hours before sleep.

In certain embodiments, the present invention provides a method of reducing PTSD symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, formulation, _{C max,} and about 22 to about 26 hours after about 1 to about 5ng administration of approximately 1.0 ng / ml to about 30.0ng / ml of cyclobenzaprine after about 2 to about 5.0 hours of dosing This results in a minimum plasma concentration of 1 / ml and provides a method wherein the composition is administered in a single daily dose for 4 or more days and is administered within 2 hours before sleep.

In some embodiments, the present invention is a method of reducing symptoms of muscle spasm including local pain and exercise restriction and acute painful musculoskeletal status in a human patient, comprising: cyclobenzaprine or a salt thereof Administering a transmucosal dosage formulation comprising 2 to about 20 mg, wherein said formulation comprises about 1.0 ng / ml to about 30.0 ng / ml of cyclobenzaprine about 2 to about 5.0 hours after administration. Provide a way to bring C _max .

  In some embodiments, the present invention is a composition for transmucosal administration comprising amitriptyline, comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein said formulation comprises about 0.05 to about 0.05 of the dose. About 20 to about 200 ng / mL amitryptyline C after 2.5 hours_maxAnd a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition provides a composition administered once daily for four or more days. In some embodiments, the present invention is a composition for transmucosal administration comprising amitriptyline, comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein said formulation comprises about 0.05 to about 0.05 of the dose. After 5 hours, a C of about 20 to about 200 ng / mL amitriptyline_maxAnd a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition provides a composition administered once daily for four or more days.
  For example, the following items are provided in the embodiment of the present invention.
(Item 1)
  A composition comprising cyclobenzaprine which is suitable for transmucosal absorption.
(Item 2)
  A composition comprising cyclobenzaprine and a basifying agent, which is suitable for transmucosal absorption.
(Item 3)
  A composition comprising amitriptyline which is suitable for transmucosal absorption.
(Item 4)
  A composition comprising amitriptyline and a basifying agent, which is suitable for transmucosal absorption.
(Item 5)
  The above-mentioned basifying agent is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, phosphoric acid An item selected from the group consisting of disodium hydrogen, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate The composition according to any one of 2 and 4.
(Item 6)
  The composition according to any one of the preceding claims, wherein the transmucosal absorption is oral absorption.
(Item 7)
  The composition according to item 6, which is suitable for sublingual administration.
(Item 8)
  8. The composition according to item 7, which is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder and a sublingual spray solution.
(Item 9)
  7. The composition according to item 6, which is suitable for buccal administration.
(Item 10)
  10. The composition according to item 9, which is in a form selected from the group consisting of an oral tablet, a lozenge, an oral tablet, and an oral spray solution.
(Item 11)
  The composition according to any one of the preceding claims, wherein said transmucosal absorption is intranasal absorption. (Item 12)
  A composition according to item 11, which is a composition in the form of a nasal spray solution.
(Item 13)
  6. The composition according to any one of the preceding items, wherein the transmucosal absorption is transpulmonary absorption.
(Item 14)
  14. The composition according to item 13, which is a composition in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.
(Item 15)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.1 ± 25% × 10 15 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 16)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.5 ± 25% × 10 30 minutes after administration.^-7mL^-1More than dnC^*16. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 17)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.5 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*17. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 18)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 4.0 ± 25% × 10 1 hour after administration.^-7mL^-1More than dnC^*18. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 19)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.2 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*19. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 20)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 9.0 ± 25% × 10 3 hours after administration.^-6mL^-1More than dnC^*20. A composition according to any one of the preceding items, characterized in that it comprises
(Item 21)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 10 hours after administration.^-7mL^-1DnC below^*Item 21. The composition according to any one of items 1 to 20, which comprises:
(Item 22)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 12 hours after administration.^-7mL^-1DnC below^*22. A composition according to any one of the preceding items, characterized in that it comprises
(Item 23)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 14 hours after administration.^-7mL^-1DnC below^*23. The composition according to any one of the preceding items, characterized in that it comprises:
(Item 24)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 16 hours after administration.^-7mL^-1DnC below^*24. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 25)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 18 hours after administration.^-7mL^-1DnC below^*25. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 26)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.02 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-20 min}, 0.05 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-30 min}0.14 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-45 min}, 0.26 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-1h, 0.87 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-2h, Or 1.23 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0 to 2.5 h}26. A composition according to any one of the preceding items, characterized in that it comprises
(Item 27)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 20 mL^-1・ Hr^-1More than dnAUC_0-∞h27. A composition according to any one of the preceding items, characterized in that it comprises
(Item 28)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10^-6mL^-1More than dnC_max ^*28. A composition according to any one of the preceding items, characterized in that it comprises
(Item 29)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered four hours after administration._max29. Composition according to any one of the preceding items, characterized in that it has a plasma concentration of 50% or less of.
(Item 30)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 6 hours after administration._max30. The composition according to any one of the preceding items, characterized in that it has a plasma concentration of 50% or less of.
(Item 31)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 8 hours after administration._max31. The composition according to any one of the preceding items, characterized in that it has a plasma concentration of 50% or less of.
(Item 32)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered 12 hours after administration._max32. A composition according to any one of the preceding items, characterized in that it has a plasma concentration of 50% or less of.
(Item 33)
  Item 33. The composition according to any one of items 1 to 32, wherein said cyclobenzaprine is present in an amount of 0.1 mg to 10 mg.
(Item 34)
  34. The composition according to item 33, wherein said cyclobenzaprine is present in an amount of 0.1 mg to 5 mg.
(Item 35)
  35. The composition according to item 34, wherein said cyclobenzaprine is present in an amount of about 2.4 mg. (Item 36)
  35. The composition according to item 34, wherein said cyclobenzaprine is present in an amount of less than about 2.4 mg.
(Item 37)
  35. The composition according to item 34, wherein said cyclobenzaprine is present in an amount of about 4.8 mg. (Item 38)
  35. The composition according to item 34, wherein said cyclobenzaprine is present in an amount of less than about 4.8 mg.
(Item 39)
  When administered by transmucosal absorption, C of cyclobenzaprine at least 10 ng / mL_max39. A composition according to any one of the preceding items, which results in
(Item 40)
  When administered by transmucosal absorption, C of cyclobenzaprine at least 15 ng / mL_max40. A composition according to item 39, which results in
(Item 41)
  20 ng / mL or more of cyclobenzaprine C when administered by transmucosal absorption_max40. A composition according to item 40, characterized in that
(Item 42)
  When administered by transmucosal absorption, C at 25 ng / mL or more of cyclobenzaprine_max42. A composition according to item 41, which results in
(Item 43)
  When administered by transmucosal absorption, C of more than 30 ng / mL of cyclobenzaprine_maxThe composition according to item 42, characterized in that
(Item 44)
  When administered by transmucosal absorption, C of cyclobenzaprine which is more than 10 ng / mL or more above baseline levels of cyclobenzaprine in the individual just before administration_max44. A composition according to any one of the preceding items, which results in
(Item 45)
  When administered by transmucosal absorption, C of cyclobenzaprine which exceeds baseline levels of cyclobenzaprine by 15 ng / mL or more in the individual just prior to administration._max45. A composition according to item 44, which results in
(Item 46)
  When administered by transmucosal absorption, C of cyclobenzaprine which exceeds baseline levels of cyclobenzaprine by 20 ng / mL or more in the individual just prior to administration._max46. A composition according to item 45, which results in
(Item 47)
  When administered by transmucosal absorption, C of cyclobenzaprine which is 25 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration._max47. A composition according to item 46, characterized in that it results in
(Item 48)
C of cyclobenzaprine above the baseline level of cyclobenzaprine in the individual just prior to dosing when administered by transmucosal absorption._max50. A composition according to item 47, which results in
(Item 49)
  Cyclobenzaprine t less than 4 hours when administered by transmucosal absorption_max50. A composition according to any one of the preceding items, which results in
(Item 50)
  Cyclobenzaprine t less than 3 hours when administered by transmucosal absorption_max50. A composition according to item 49, which results in
(Item 51)
  Cyclobenzaprine t less than 2 hours when administered by transmucosal absorption_max50. A composition according to item 50, which results in
(Item 52)
  Cyclobenzaprine t less than 1 hour when administered by transmucosal absorption_max56. A composition according to item 51, which results in
(Item 53)
  Less than 45 minutes of cyclobenzaprine t when administered by transmucosal absorption_max54. A composition according to item 52, which results in
(Item 54)
  Less than 30 minutes of cyclobenzaprine t when administered by transmucosal absorption_max54. A composition according to item 53, which results in
(Item 55)
  Less than 15 minutes of cyclobenzaprine t when administered by transmucosal absorption_max55. A composition according to item 54, which results in
(Item 56)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max56. A composition according to any one of the preceding items, characterized in that it results in at least 50% of the plasma levels of cyclobenzaprine being reduced.
(Item 57)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max57. A composition according to item 56, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 60% of.
(Item 58)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max58. A composition according to item 57, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 70% of.
(Item 59)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max59. A composition according to item 58, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 80% of.
(Item 60)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max60. The composition according to item 59, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 90%.
(Item 61)
  When administered by transmucosal absorption, the above C by 8 hours after administration._max61. A composition according to item 60, characterized in that it results in at least 95% of the plasma levels of cyclobenzaprine being reduced.
(Item 62)
  A method of treating a disease or condition in an individual in need of treatment of the disease or condition comprising administering the composition according to any one of paragraphs 1 to 61 by transmucosal absorption.
(Item 63)
  The method according to item 62, wherein the disease or condition is post-traumatic stress disorder (PTSD).
(Item 64)
  The method according to item 63, wherein the administration of the composition treats the onset of PTSD after a trauma event.
(Item 65)
  64. A method according to item 63, wherein the administration of the composition treats the onset of PTSD after a trauma event.
(Item 66)
  64. A method according to item 63, wherein the administration of the composition treats the intensification of PTSD after a trauma event.
(Item 67)
  The method according to item 63, wherein the administration of the composition treats the persistence of PTSD after a trauma event.
(Item 68)
  73. The method according to item 62, wherein said disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, muscle spasm and anxiety disorder .
(Item 69)
  The above-mentioned basifying agent is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, phosphoric acid An item selected from the group consisting of disodium hydrogen, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate The method according to any one of 62 to 68.
(Item 70)
  70. The method according to any one of items 62 to 69, wherein the oral absorption is sublingual absorption.
(Item 71)
  71. The method according to item 70, wherein the composition is a composition in a form selected from the group consisting of sublingual tablet, sublingual film, sublingual powder, and sublingual spray solution.
(Item 72)
  70. A method according to any one of items 62 to 69, wherein the oral absorption is buccal absorption. (Item 73)
  73. A method according to item 72, wherein the composition is selected from the group consisting of buccal tablets, lozenges, buccal tablets, and buccal spray solutions.
(Item 74)
  73. A method according to any one of items 62 to 73, wherein the transmucosal absorption is intranasal absorption.
(Item 75)
  76. A method according to item 74, wherein said composition is a composition in the form of a nasal spray solution.
(Item 76)
  73. A method according to any one of items 62 to 73, wherein the transmucosal absorption is transpulmonary absorption. (Item 77)
  79. A method according to item 76, wherein the composition is a composition in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.
(Item 78)
  The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 79)
  The cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7mL^-1More than dnC^*79. A method according to any one of clauses 62 to 78, comprising:
(Item 80)
  The cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*80. A method according to any one of items 62 to 79, having
(Item 81)
  The cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 1 hour after administration.^-7mL^-1More than dnC^*91. A method according to any one of items 62 to 80, having
(Item 82)
  The above cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*92. A method according to any one of items 62 to 81, having
(Item 83)
  The cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*92. A method according to any one of items 62 to 82, having
(Item 84)
  The said cyclobenzaprine or amitriptyline is 8.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*93. A method according to any one of items 62 to 83, having
(Item 85)
  The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 12 hours after administration.^-7mL^-1DnC below^*92. A method according to any one of items 62 to 84, having
(Item 86)
  The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 14 hours after administration.^-7mL^-1DnC below^*The method according to any one of the items 62 to 85, having
(Item 87)
  The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 16 hours after administration.^-7mL^-1DnC below^*96. A method according to any one of items 62 to 86, having
(Item 88)
  The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 18 hours after administration.^-7mL^-1DnC below^*92. A method according to any one of items 62 to 87, having
(Item 89)
  The said cyclobenzaprine or amitriptyline is 0.02 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-20 min}, 0.05 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-30 min}0.14 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-45 min}, 0.26 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-1h, 0.87 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-2h, Or 1.23 ± 25% × 10^-6hr · mL^-11More than dnAUC_{0 to 2.5 h}89. A method according to any one of items 62 to 88, having
(Item 90)
  20 mL of the cyclobenzaprine or amitriptyline^-1・ Hr^-1More than dnAUC_0-∞h90. A method according to any one of items 62 to 89, having
(Item 91)
  The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10^-6mL^-1More than dnC_max ^*The method according to any one of items 62 to 90, comprising:
(Item 92)
  The cyclobenzaprine or amitriptyline is administered four hours after administration._max92. A method according to any one of items 62 to 91, having a plasma concentration of 50% or less of.
(Item 93)
  The cyclobenzaprine or amitriptyline is administered 6 hours after administration._max92. A method according to any one of items 62 to 92, having a plasma concentration of 50% or less of.
(Item 94)
  The cyclobenzaprine or amitriptyline is administered at 8 hours after administration._max100. A method according to any one of items 62 to 93, having a plasma concentration of 50% or less of.
(Item 95)
  The cyclobenzaprine or amitriptyline is administered 12 hours after administration._max95. A method according to any one of items 62 to 94, having a plasma concentration of 50% or less of.
(Item 96)
  96. A method according to any one of items 62 to 95, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 10 mg.
(Item 97)
  97. The method of paragraph 96, wherein said cyclobenzaprine is present in said composition in an amount of 0.1 mg to 5 mg.
(Item 98)
  100. The method of paragraph 97, wherein said cyclobenzaprine is present in said composition in an amount of about 2.4 mg.
(Item 99)
  100. The method of paragraph 98, wherein said cyclobenzaprine is present in an amount of less than about 2.4 mg.
(Item 100)
  100. The method of paragraph 99, wherein said cyclobenzaprine is present in an amount of about 4.8 mg.
(Item 101)
  111. The method according to item 100, wherein said cyclobenzaprine is present in an amount of less than about 4.8 mg.
(Item 102)
  The composition has a C of cyclobenzaprine of 10 ng / mL or more._maxThe method according to any one of items 62 to 101, which results in
(Item 103)
  The composition has a C of cyclobenzaprine of 15 ng / mL or more._maxThe method according to item 102, resulting in
(Item 104)
  The composition has a C of cyclobenzaprine of at least 20 ng / mL._maxThe method according to item 103, which brings about.
(Item 105)
  The composition has a C of cyclobenzaprine of 25 ng / mL or more._maxThe method according to item 104, which brings about.
(Item 106)
  The composition has a C of at least 30 ng / mL of cyclobenzaprine_maxThe method according to item 105, which brings about.
(Item 107)
  The composition has a C of cyclobenzaprine which is 10 ng / mL or more above the baseline level of cyclobenzaprine in the individual just prior to administration._maxThe method according to any one of items 62 to 106, which results in
(Item 108)
  The composition has a C of cyclobenzaprine which is 15 ng / mL or more above the baseline level of cyclobenzaprine in the individual just prior to administration._maxThe method according to item 107, which brings about.
(Item 109)
  The composition has a C of cyclobenzaprine that is 20 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration_maxThe method according to item 108, resulting in
(Item 110)
  The composition has a C of cyclobenzaprine which is 25 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration_maxThe method according to item 109, which brings about.
(Item 111)
  The composition has a C of cyclobenzaprine above the baseline level of cyclobenzaprine by 30 ng / mL or more in the individual immediately before administration._maxA method according to item 110, which brings about.
(Item 112)
  Said composition is less than 4 hours of cyclobenzaprine t_maxThe method according to any one of items 62 to 111, which results in
(Item 113)
  Said composition is less than 3 hours of cyclobenzaprine t_maxThe method according to item 112, which brings about.
(Item 114)
  Said composition has less than 2 hours of cyclobenzaprine t_maxThe method according to item 113, which brings about.
(Item 115)
  Said composition is less than 1 hour of cyclobenzaprine t_max114. A method according to item 114 which brings
(Item 116)
  Said composition is less than 45 minutes of cyclobenzaprine t_maxThe method according to item 115, which brings about.
(Item 117)
  Said composition is less than 30 minutes of cyclobenzaprine t_maxThe method according to item 116, which brings about.
(Item 118)
  Said composition is less than 15 minutes of cyclobenzaprine t_maxThe method according to item 117, which brings about.
(Item 119)
  Said composition by 8 hours after administration of said C_max119. A method according to any one of items 62 to 118, which results in plasma levels of cyclobenzaprine being reduced by at least 50% of.
(Item 120)
  Said composition by 8 hours after administration of said C_max120. A method according to item 119, which results in plasma levels of cyclobenzaprine being reduced by at least 60% of
(Item 121)
  Said composition by 8 hours after administration of said C_max120. A method according to item 120, which results in plasma levels of cyclobenzaprine being reduced by at least 70% of
(Item 122)
  Said composition by 8 hours after administration of said C_max126. A method according to item 121, which results in plasma levels of cyclobenzaprine being reduced by at least 80% of
(Item 123)
  Said composition by 8 hours after administration of said C_max124. A method according to item 122, which results in plasma levels of cyclobenzaprine being reduced by at least 90% of
(Item 124)
  Said composition by 8 hours after administration of said C_max124. A method according to item 123, which results in plasma levels of cyclobenzaprine being reduced by at least 95% of
(Item 125)
  A composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein said formulation comprises from about 0.05 to about 2.5 hours of administration. And after about 20 to about 200 ng / mL of cyclobenzaprine C_maxAnd a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered in a single daily dose for 4 days or more.
(Item 126)
  A method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, said formulation comprising about 0 of the administration. From about 20 to about 200 ng / mL of cyclobenzaprine C._maxAnd a minimum plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered once daily for four days or more and within two hours before sleep Administered to the patient.
(Item 127)
  A composition for transmucosal administration comprising amitriptyline comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein said formulation comprises about 20 to about 200 ng after about 0.05 to about 2.5 hours of administration. / ML amitriptyline C_maxAnd a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered in a single daily dose for 4 days or more.
(Item 128)
  A method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 25 mg of amitriptyline or a salt thereof, said formulation comprising about 0.05 of the administration. -About 2.5 hours after about 20 to about 200 ng / mL amitriptyline C_maxAnd a minimum plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered once daily for four days or more and within two hours before sleep Administered to the patient.
(Item 129)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 130)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 157.60 × 10 20 minutes after administration.^-9mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 131)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7DnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 132)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 133)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 60 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 134)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 135)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 6.5 ± 25% × 10 5 after 2.5 hours of administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 136)
  When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding items, characterized in that it comprises:
(Item 137)
  The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of 2.8 mg.
(Item 138)
  The composition according to any one of items 1 to 32, wherein the cyclobenzaprine is present in an amount of 5.6 mg.
(Item 139)
  34. The composition according to any one of the clauses, wherein the cyclobenzaprine is present in an amount of less than about 9 mg.
(Item 140)
  The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 141)
  The cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 142)
  The cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 143)
  The cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 1 hour after administration.^-7More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 144)
  The above cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 145)
  The cyclobenzaprine or amitriptyline is 6.5 ± 25% × 10 2.5 hours after administration.^-7mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 146)
  The cyclobenzaprine or amitriptyline is 727.67 ± 25% × 10 2.5 hours after administration.^-9mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 147)
  The cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*78. A method according to any one of clauses 62 to 77, comprising:
(Item 148)
  When administered by transmucosal absorption, C of cyclobenzaprine greater than 2 ng / mL_max39. A composition according to any one of the preceding items, which results in
(Item 149)
  When administered by transmucosal absorption, C of cyclobenzaprine which is more than 2 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration._max44. A composition according to any one of the preceding items, which results in

  In some embodiments, the invention comprises a method of reducing fibromyalgia symptoms in a human patient comprising administering a transmucosal dosage formulation comprising about 2 to about 25 mg of amitriptyline or a salt thereof, The formulation comprises about 20 to about 200 ng / mL of amitriptyline C from about 0.05 to about 2.5 hours after administration._maxAnd a minimum plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered once daily for 4 days or more and administered within 2 hours before sleep Provide a method that will In some embodiments, the present invention is a method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 7.5 to about 50 mg of amitriptyline or a salt thereof. Said formulation containing about 3 to about 90 ng / ml of amitryptyline C from about 2 to about 5 hours after administration._maxAnd a minimum amitriptyline plasma concentration of about 3 to about 15 ng / ml after about 22 to about 26 hours of administration, providing a method wherein the composition is administered once daily for 4 days or more.
  Some embodiments of the invention are as follows:
  1. A composition comprising cyclobenzaprine which is suitable for transmucosal absorption.
  2. A composition comprising cyclobenzaprine and a basifying agent, which is suitable for transmucosal absorption.
  3. A composition comprising amitriptyline which is suitable for transmucosal absorption.
  4. A composition comprising amitriptyline and a basifying agent, which is suitable for transmucosal absorption.
  5. The above-mentioned basifying agent is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, phosphoric acid Selected from the group consisting of disodium hydrogen, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate, The composition according to any one of Forms 2 and 4.
  6. The composition according to any one of the preceding embodiments, wherein the transmucosal absorption is oral absorption.
  7. The composition according to embodiment 6, which is suitable for sublingual administration.
  8. Embodiment 7. The composition according to embodiment 7, which is in a form selected from the group consisting of a sublingual tablet, a sublingual film, a sublingual powder, and a sublingual spray solution.
  9. Embodiment 7. The composition according to embodiment 6, which is suitable for buccal administration.
  10. Embodiment 10. The composition according to embodiment 9, which is in a form selected from the group consisting of an oral tablet, a lozenge, an oral tablet, and an oral spray solution.
  11. The composition according to any one of the preceding embodiments, wherein the transmucosal absorption is intranasal absorption.
  12. The composition according to embodiment 11, which is a composition in the form of a nasal spray solution.
  13. The composition according to any one of the preceding embodiments, wherein the transmucosal absorption is transpulmonary absorption.
  14. The composition according to embodiment 13, which is a composition in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.
  15. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.1 ± 25% × 10 15 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  16. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.5 ± 25% × 10 30 minutes after administration.^-7mL^-1More than dnC^*The composition according to any one of the embodiments 1-15, characterized in that it comprises
  17. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.5 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*17. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  18. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 4.0 ± 25% × 10 1 hour after administration.^-7mL^-1More than dnC^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  19. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.2 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  20. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 9.0 ± 25% × 10 3 hours after administration.^-6mL^-1More than dnC^*20. The composition according to any one of the preceding embodiments, characterized in that it comprises:
  21. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 10 hours after administration.^-7mL^-1DnC below^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  22. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 12 hours after administration.^-7mL^-1DnC below^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  23. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 14 hours after administration.^-7mL^-1DnC below^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  24. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 16 hours after administration.^-7mL^-1DnC below^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  25. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 18 hours after administration.^-7mL^-1DnC below^*The composition according to any one of the preceding embodiments, characterized in that it comprises
  26. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 0.02 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-20 min}, 0.05 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-30 min}0.14 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-45 min}, 0.26 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-1h, 0.87 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-2h, Or 1.23 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0 to 2.5 h}The composition according to any one of the preceding embodiments, characterized in that it comprises
  27. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 20 mL^-1・ Hr^-1More than dnAUC_0-∞h27. The composition according to any one of the embodiments 1 to 26, characterized in that it comprises:
  28. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10^-6mL^-1More than dnC_max ^*The composition according to any one of the embodiments 1-27, characterized in that it comprises
  29. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered four hours after administration._max29. The composition according to any one of the embodiments 1 to 28, characterized in that it has a plasma concentration of 50% or less of.
  30. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 6 hours after administration._maxThe composition according to any one of the preceding embodiments, characterized in that it has a plasma concentration of 50% or less of
  31. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 8 hours after administration._maxThe composition according to any one of the preceding embodiments, characterized in that it has a plasma concentration of 50% or less of
  32. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered 12 hours after administration._max32. The composition according to any one of the embodiments 1-31, characterized in that it has a plasma concentration of 50% or less of.
  33. Embodiment 33. The composition according to any one of the embodiments 1 to 32, wherein said cyclobenzaprine is present in an amount of 0.1 mg to 10 mg.
  34. The composition according to embodiment 33, wherein said cyclobenzaprine is present in an amount of 0.1 mg to 5 mg.
  35. The composition according to embodiment 34, wherein said cyclobenzaprine is present in an amount of about 2.4 mg.
  36. The composition according to embodiment 34, wherein the cyclobenzaprine is present in an amount of less than about 2.4 mg.
  37. The composition according to embodiment 34, wherein said cyclobenzaprine is present in an amount of about 4.8 mg.
  38. The composition according to embodiment 34, wherein said cyclobenzaprine is present in an amount of less than about 4.8 mg.
  39. When administered by transmucosal absorption, C of cyclobenzaprine at least 10 ng / mL_maxEmbodiment 39. The composition according to any one of the embodiments 1-38, which results in
  40. When administered by transmucosal absorption, C of cyclobenzaprine at least 15 ng / mL_maxEmbodiment 40. The composition according to embodiment 39, characterized in that
  41. 20 ng / mL or more of cyclobenzaprine C when administered by transmucosal absorption_maxThe composition according to embodiment 40, characterized in that
  42. When administered by transmucosal absorption, C at 25 ng / mL or more of cyclobenzaprine_maxThe composition according to embodiment 41, characterized in that
  43. When administered by transmucosal absorption, C of more than 30 ng / mL of cyclobenzaprine_maxEmbodiment 42. The composition according to embodiment 42, characterized in that
  44. When administered by transmucosal absorption, C of cyclobenzaprine which is more than 10 ng / mL or more above baseline levels of cyclobenzaprine in the individual just before administration_maxEmbodiment 45. The composition according to any one of the embodiments 1-43, characterized in that
  45. When administered by transmucosal absorption, C of cyclobenzaprine which exceeds baseline levels of cyclobenzaprine by 15 ng / mL or more in the individual just prior to administration._maxEmbodiment 45. The composition according to embodiment 44, characterized in that
  46. When administered by transmucosal absorption, C of cyclobenzaprine which exceeds baseline levels of cyclobenzaprine by 20 ng / mL or more in the individual just prior to administration._max46. The composition according to embodiment 45, which results in
  47. When administered by transmucosal absorption, C of cyclobenzaprine which is 25 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration._maxEmbodiment 47. The composition according to embodiment 46, characterized in that
  48. C of cyclobenzaprine above the baseline level of cyclobenzaprine in the individual just prior to dosing when administered by transmucosal absorption._maxEmbodiment 50. The composition according to embodiment 47, which results in
  49. Cyclobenzaprine t less than 4 hours when administered by transmucosal absorption_maxThe composition according to any one of the embodiments 1-48, which results in
  50. Cyclobenzaprine t less than 3 hours when administered by transmucosal absorption_maxEmbodiment 50. The composition according to embodiment 49, which results in
  51. Cyclobenzaprine t less than 2 hours when administered by transmucosal absorption_maxThe composition according to embodiment 50, characterized in that
  52. Cyclobenzaprine t less than 1 hour when administered by transmucosal absorption_max52. The composition according to embodiment 51, which results in
  53. Less than 45 minutes of cyclobenzaprine t when administered by transmucosal absorption_maxThe composition according to embodiment 52, characterized in that it results in
  54. Less than 30 minutes of cyclobenzaprine t when administered by transmucosal absorption_maxThe composition according to embodiment 53, characterized in that
  55. Less than 15 minutes of cyclobenzaprine t when administered by transmucosal absorption_maxEmbodiment 55. The composition according to embodiment 54, which results in
  56. When administered by transmucosal absorption, the above C by 8 hours after administration._max56. The composition according to any one of the embodiments 1-55, characterized in that it results in at least 50% of the plasma levels of cyclobenzaprine being reduced.
  57. When administered by transmucosal absorption, the above C by 8 hours after administration._maxEmbodiment 56. The composition according to embodiment 56, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 60% of.
  58. When administered by transmucosal absorption, the above C by 8 hours after administration._maxEmbodiment 57. The composition according to embodiment 57, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 70%.
  59. When administered by transmucosal absorption, the above C by 8 hours after administration._max59. The composition according to embodiment 58, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 80% of.
  60. When administered by transmucosal absorption, the above C by 8 hours after administration._maxEmbodiment 60. The composition according to embodiment 59, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 90%.
  61. When administered by transmucosal absorption, the above C by 8 hours after administration._max61. The composition according to embodiment 60, characterized in that it results in plasma levels of cyclobenzaprine being reduced by at least 95%.
  62. A method of treating a disease or condition in an individual in need of treatment of the disease or condition comprising administering the composition according to any one of the embodiments 1-61 by transmucosal absorption.
  63. Embodiment 63. The method according to embodiment 62, wherein the disease or condition is post-traumatic stress disorder (PTSD).
  64. Embodiment 64. The method according to embodiment 63, wherein the administration of the composition treats the onset of PTSD after a trauma event.
  65. Embodiment 64. The method according to embodiment 63, wherein the administration of the composition treats the onset of PTSD after a trauma event.
  66. Embodiment 64. The method according to embodiment 63, wherein the administration of the composition treats an enhancement of PTSD after a trauma event.
  67. Embodiment 64. The method according to embodiment 63, wherein administration of the composition treats persistence of PTSD after a trauma event.
  68. Embodiment 69. The embodiment according to embodiment 62, wherein said disease or condition is selected from the group consisting of fibromyalgia, depression, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, muscle spasm and anxiety disorder. Method.
  69. The above-mentioned basifying agent is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, phosphoric acid Selected from the group consisting of disodium hydrogen, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate, The method of any one of Forms 62-68.
  70. 70. The method according to any one of the embodiments 62-69, wherein the oral absorption is sublingual absorption.
  71. Embodiment 70. The method according to embodiment 70, wherein the composition is a composition in a form selected from the group consisting of sublingual tablet, sublingual film, sublingual powder, and sublingual spray solution.
  72. 70. The method of any one of embodiments 62-69, wherein said oral absorption is buccal absorption.
  73. Embodiment 73. The method according to embodiment 72, wherein the composition is selected from the group consisting of buccal tablets, lozenges, buccal tablets, and buccal spray solutions.
  74. Embodiment 74. The method of any one of embodiments 62-73, wherein the transmucosal absorption is intranasal absorption.
  75. Embodiment 75. The method according to embodiment 74, wherein said composition is a composition in the form of a nasal spray solution.
  76. Embodiment 74. The method of any one of embodiments 62-73, wherein the transmucosal absorption is transpulmonary absorption.
  77. Embodiment 77. The method according to embodiment 76, wherein said composition is a composition in a form selected from the group consisting of an aerosolized composition and an inhalable dry powder.
  78. The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  79. The cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7mL^-1More than dnC^*Embodiment 79. The method according to any one of the embodiments 62-78.
  80. The cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*80. The method according to any one of the embodiments 62-79, wherein
  81. The cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 1 hour after administration.^-7mL^-1More than dnC^*The method according to any one of the embodiments 62-80, having the
  82. The above cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*Embodiment 82. The method according to any one of the embodiments 62-81.
  83. The cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*Embodiment 83. The method according to any one of the embodiments 62-82.
  84. The said cyclobenzaprine or amitriptyline is 8.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*Embodiment 84. The method according to any one of the embodiments 62-83.
  85. The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 12 hours after administration.^-7mL^-1DnC below^*The method according to any one of the embodiments 62-84, having
  86. The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 14 hours after administration.^-7mL^-1DnC below^*The method according to any one of the embodiments 62-85, having
  87. The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 16 hours after administration.^-7mL^-1DnC below^*The method according to any one of the embodiments 62-86, having the
  88. The cyclobenzaprine or amitriptyline is 5.0 ± 25% × 10 18 hours after administration.^-7mL^-1DnC below^*The method according to any one of the embodiments 62-87, having
  89. The said cyclobenzaprine or amitriptyline is 0.02 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-20 min}, 0.05 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-30 min}0.14 ± 25% × 10^-6hr · mL^-1More than dnAUC_{0-45 min}, 0.26 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-1h, 0.87 ± 25% × 10^-6hr · mL^-1More than dnAUC_0-2h, Or 1.23 ± 25% × 10^-6hr · mL^-11More than dnAUC_{0 to 2.5 h}Embodiment 90. The method according to any one of the embodiments 62-88.
  90. 20 mL of the cyclobenzaprine or amitriptyline^-1・ Hr^-1More than dnAUC_0-∞hThe method according to any one of the embodiments 62-89, having
  91. The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10^-6mL^-1More than dnC_max ^*Embodiment 90. The method according to any one of the embodiments 62-90, wherein
  92. The cyclobenzaprine or amitriptyline is administered four hours after administration._maxThe method according to any one of the embodiments 62-91, having a plasma concentration of 50% or less of
  93. The cyclobenzaprine or amitriptyline is administered 6 hours after administration._maxThe method according to any one of the embodiments 62-92, having a plasma concentration of 50% or less of
  94. The cyclobenzaprine or amitriptyline is administered at 8 hours after administration._maxThe method according to any one of the embodiments 62-93, having a plasma concentration of 50% or less of
  95. The cyclobenzaprine or amitriptyline is administered 12 hours after administration._maxThe method according to any one of the embodiments 62-94, having a plasma concentration of 50% or less of
  96. The method according to any one of the embodiments 62 to 95, wherein the cyclobenzaprine is present in the composition in an amount of 0.1 mg to 10 mg.
  97. Embodiment 97. The method according to embodiment 96, wherein said cyclobenzaprine is present in said composition in an amount of 0.1 mg to 5 mg.
  98. Embodiment 97. The method according to embodiment 97, wherein said cyclobenzaprine is present in said composition in an amount of about 2.4 mg.
  99. 99. The method of embodiment 98 wherein said cyclobenzaprine is present in an amount of less than about 2.4 mg.
  100. Embodiment 100. The method according to embodiment 99, wherein said cyclobenzaprine is present in an amount of about 4.8 mg.
  101. The method of embodiment 100 wherein said cyclobenzaprine is present in an amount of less than about 4.8 mg.
  102. The composition has a C of cyclobenzaprine of 10 ng / mL or more._maxThe method according to any one of the embodiments 62-101, which results in
  103. The composition has a C of cyclobenzaprine of 15 ng / mL or more._maxThe method of embodiment 102, which results in
  104. The composition has a C of cyclobenzaprine of at least 20 ng / mL._maxThe method of embodiment 103, which results in
  105. The composition has a C of cyclobenzaprine of 25 ng / mL or more._maxThe method of embodiment 104, wherein
  106. The composition has a C of at least 30 ng / mL of cyclobenzaprine_maxThe method of embodiment 105, which results in
  107. The composition has a C of cyclobenzaprine which is 10 ng / mL or more above the baseline level of cyclobenzaprine in the individual just prior to administration._maxThe method according to any one of the embodiments 62-106, which results in
  108. The composition has a C of cyclobenzaprine which is 15 ng / mL or more above the baseline level of cyclobenzaprine in the individual just prior to administration._maxThe method of embodiment 107, which results in
  109. The composition has a C of cyclobenzaprine that is 20 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration_max109. The method of embodiment 108, wherein
  110. The composition has a C of cyclobenzaprine which is 25 ng / mL or more above the baseline level of cyclobenzaprine in the individual immediately before administration_maxThe method of embodiment 109, which results in
  111. The composition has a C of cyclobenzaprine above the baseline level of cyclobenzaprine by 30 ng / mL or more in the individual immediately before administration._maxThe method according to embodiment 110, which results in
  112. Said composition is less than 4 hours of cyclobenzaprine t_maxThe method according to any one of the embodiments 62-111, which results in
  113. Said composition is less than 3 hours of cyclobenzaprine t_max112. The method of embodiment 112, which results in
  114. Said composition has less than 2 hours of cyclobenzaprine t_maxThe method of embodiment 113, which results in
  115. Said composition is less than 1 hour of cyclobenzaprine t_max115. The method of embodiment 114, which results in
  116. Said composition is less than 45 minutes of cyclobenzaprine t_maxThe method of embodiment 115, which results in
  117. Said composition is less than 30 minutes of cyclobenzaprine t_maxThe method according to embodiment 116, which results in
  118. Said composition is less than 15 minutes of cyclobenzaprine t_maxThe method of embodiment 117, which results in
  119. Said composition by 8 hours after administration of said C_max119. The method according to any one of the embodiments 62-118, wherein at least 50% of the results in reduced plasma levels of cyclobenzaprine.
  120. Said composition by 8 hours after administration of said C_maxEmbodiment 120. The method according to embodiment 119, which results in plasma levels of cyclobenzaprine being reduced by at least 60% of
  121. Said composition by 8 hours after administration of said C_maxEmbodiment 120. The method according to embodiment 120, which results in plasma levels of cyclobenzaprine being reduced by at least 70%.
  122. Said composition by 8 hours after administration of said C_maxThe method according to embodiment 121, which results in plasma levels of cyclobenzaprine being reduced by at least 80% of
  123. Said composition by 8 hours after administration of said C_maxEmbodiment 123. The method according to embodiment 122, which results in plasma levels of cyclobenzaprine being reduced by at least 90%.
  124. Said composition by 8 hours after administration of said C_maxEmbodiment 124. The method according to embodiment 123, which results in plasma levels of cyclobenzaprine being reduced by at least 95%.
  125. A composition for transmucosal administration comprising cyclobenzaprine comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, wherein said formulation comprises from about 0.05 to about 2.5 hours of administration. And after about 20 to about 200 ng / mL of cyclobenzaprine C_maxAnd a minimum cyclobenzaprine plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered in a single daily dose for 4 days or more.
  126. A method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 20 mg of cyclobenzaprine or a salt thereof, said formulation comprising about 0 of the administration. From about 20 to about 200 ng / mL of cyclobenzaprine C._maxAnd a minimum plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered once daily for four days or more and within two hours before sleep Administered to the patient.
  127. A composition for transmucosal administration comprising amitriptyline comprising about 2 to about 25 mg of amitriptyline or a salt thereof, wherein said formulation comprises about 20 to about 200 ng after about 0.05 to about 2.5 hours of administration. / ML amitriptyline C_maxAnd a minimum amitriptyline plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered in a single daily dose for 4 days or more.
  128. A method of reducing fibromyalgia symptoms in a human patient, comprising administering a transmucosal dosage formulation comprising about 2 to about 25 mg of amitriptyline or a salt thereof, said formulation comprising about 0.05 of the administration. -About 2.5 hours after about 20 to about 200 ng / mL amitriptyline C_maxAnd a minimum plasma concentration of about 1 to about 5 ng / mL after about 22 to about 26 hours of administration, wherein the composition is administered once daily for four days or more and within two hours before sleep Administered to the patient.
  129. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  130. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is administered at 157.60 × 10 20 minutes after administration.^-9mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  131. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7DnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  132. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  133. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 60 minutes after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  134. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  135. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 6.5 ± 25% × 10 5 after 2.5 hours of administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  136. When administered by transmucosal absorption, the cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*15. A composition according to any one of the preceding embodiments, characterized in that it comprises:
  137. Embodiment 33. The composition according to any one of the embodiments 1 to 32, wherein said cyclobenzaprine is present in an amount of 2.8 mg.
  138. Embodiment 33. The composition according to any one of embodiments 1 to 32, wherein said cyclobenzaprine is present in an amount of 5.6 mg.
  139. The composition according to any one of the embodiments 1-32, wherein said cyclobenzaprine is present in an amount of less than about 9 mg.
  140. The cyclobenzaprine or amitriptyline is 1.0 ± 25% × 10 20 minutes after administration.^-7mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  141. The cyclobenzaprine or amitriptyline is 2.5 ± 25% × 10 30 minutes after administration.^-7More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  142. The cyclobenzaprine or amitriptyline is 3.0 ± 25% × 10 5 minutes after administration.^-7More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  143. The cyclobenzaprine or amitriptyline is 4.2 ± 25% × 10 1 hour after administration.^-7More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  144. The above cyclobenzaprine or amitriptyline is 6.0 ± 25% × 10 2 hours after administration.^-7mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  145. The cyclobenzaprine or amitriptyline is 6.5 ± 25% × 10 2.5 hours after administration.^-7mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  146. The cyclobenzaprine or amitriptyline is 727.67 ± 25% × 10 2.5 hours after administration.^-9mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  147. The cyclobenzaprine or amitriptyline is 7.0 ± 25% × 10 3 hours after administration.^-7mL^-1More than dnC^*Embodiment 78. The method according to any one of the embodiments 62-77.
  148. When administered by transmucosal absorption, C of cyclobenzaprine greater than 2 ng / mL_maxEmbodiment 39. The composition according to any one of the embodiments 1-38, which results in
  149. When administered by transmucosal absorption, C of cyclobenzaprine which is more than 2 ng / mL or more above baseline levels of cyclobenzaprine in the individual just prior to administration._maxEmbodiment 45. The composition according to any one of the embodiments 1-43, characterized in that

FIG. 1 a shows mean plasma cyclobenzaprine concentrations ± standard deviation and mean plasma nociclobenzaprine in 10 healthy human subjects after oral (PO) treatment in fasted state with 5 mg cyclobenzaprine HCl immediate release tablets It is a line graph of concentration ± standard deviation.

FIG. 1 b shows mean plasma cyclobenzaprine concentrations ± standard deviation and mean plasma noricyclobenzaprine concentrations ± standards in 10 healthy human subjects after PO treatment in the fasted state with 5 mg cyclobenzaprine HCl immediate release tablets It is a logarithmic graph of deviation.

FIG. 2 is a line graph of mean cyclobenzaprine concentration ± standard deviation over time in female beagle dog plasma. Cyclobenzaprine was administered orally (PO) orally, sublingually or intravenously (IV) via the naso-gastric (NG) tube.

FIG. 3 is a semilogarithmic graph of mean cyclobenzaprine concentration ± standard deviation over time in female beagle dog plasma. Cyclobenzaprine was administered orally (PO) by NG tube, sublingually or intravenously.

FIG. 4 is a graph of mean cyclobenzaprine concentration time profile ± standard deviation after IV administration of cyclobenzaprine HCl in female beagle dog plasma, the mean of dogs treated and untreated with propofol pre-anesthetic (IV study) is compared to the mean of the dogs from the IV data of FIG.

Figure 5 is a graph of mean cyclobenzaprine concentration time profile ± standard deviation after sublingual administration of cyclobenzaprine HCl in female beagle dog plasma, in dogs pretreated with propofol and without treatment. The mean (sublingual survey) is compared to the canine average from the sublingual data in FIG.

FIG. 6 is a line graph of mean cyclobenzaprine concentration ± standard deviation over time in female beagle dog plasma. Cyclobenzaprine was administered sublingually either in tablets containing the basifying agent K ₂ HPO ₄ or in tablets lacking the basifying agent K ₂ HPO ₄ .

FIG. 7 is a log graph of mean cyclobenzaprine concentration ± standard deviation over time in female beagle dog plasma. Cyclobenzaprine was administered sublingually in tablets with or without the basifying agent K ₂ HPO ₄ .

FIG. 8 is a table showing a once-daily assessment conducted over the course of the study in which cyclobenzaprine HCl was administered to humans.

FIG. 9 is a table showing one hour evaluation performed after PO administration to humans during the study of 5 mg cyclobenzaprine HCl immediate release tablets.

Figure 10: Cyclobenzaprine plasma 0-1 hour after sublingual (SL, subject 7 only), oral (PO, group average), and intravenous (IV, group average) doses of cyclobenzaprine It is a graph which shows a concentration-time profile.

FIG. 11 shows cyclobenzaprine plasma concentration-time profiles 0-24 hours after sublingual (subject 7 only), oral (group average) and intravenous (group average) doses of cyclobenzaprine It is a graph.

Figure 12: Sublingual cyclobenzaprine at pH 7.1 (average of all subjects except subjects 7 and 10), at pH 3.5 (average of all subjects except subject 4), and orally (group average) It is a graph which shows the average cyclobenzaprine plasma concentration-time profile 0 to 24 hours after administering cyclobenzaprine in.

FIG. 13 shows norcyclobenzaprine plasma concentration-time profiles 0-24 hours after sublingual (subject 7 only), oral (group average) and intravenous (group average) doses of cyclobenzaprine FIG.

FIG. 14 is a graph showing cyclobenzaprine plasma concentrations 0 to 2 hours after sublingual cyclobenzaprine 2.4 mg (FIG. 14 a) and 4.8 mg (FIG. 14 b) and oral cyclobenzaprine 5 mg is there. FIG. 14 is a graph showing cyclobenzaprine plasma concentrations 0 to 2 hours after sublingual cyclobenzaprine 2.4 mg (FIG. 14 a) and 4.8 mg (FIG. 14 b) and oral cyclobenzaprine 5 mg is there.

FIG. 15 is a graph showing cyclobenzaprine plasma concentrations 0 to 8 hours after administration of 4.8 mg of sublingual cyclobenzaprine and 5 mg of oral cyclobenzaprine.

FIG. 16 is a graph showing cyclobenzaprine plasma concentrations 0 to 8 hours after administration of 2.4 mg and 4.8 mg of sublingual cyclobenzaprine.

FIG. 17 is a graph showing cyclobenzaprine plasma concentrations 0 to 2 hours (FIG. 17a) and 0 to 8 hours (FIG. 17b) after administration of 2.4 mg of sublingual cyclobenzaprine with or without phosphate It is. FIG. 17 is a graph showing cyclobenzaprine plasma concentrations 0 to 2 hours (FIG. 17a) and 0 to 8 hours (FIG. 17b) after administration of 2.4 mg of sublingual cyclobenzaprine with or without phosphate It is.

Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against Figure 18 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 18a; _{5-HT 2A,} FIG. 18b; _{5-HT 2B,} FIG. 18c; _{5-HT 2C,} FIG. 18 d;), histamine H ₁ (H ₁ ) (FIG. 18 e), adrenergic α _{1 A} (α _{1 A} ) (FIG. 18 f), muscarinic M ₁ (M ₁ ) (FIG. 18 g), and dopamine D ₁ (D ₁ ) (FIG. 18 h) receptors Figure 14 is a graph showing equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) against

Figure 19 shows equilibrium binding studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) on norepinephrine (NE), 5-HT, and dopamine (D) transporters expressed in the human central nervous system It is a graph.

Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles). Figure 20 is a serotonin expressed in the central nervous system of a human _{(5-HT 1A,} FIG. 20a; _{5-HT 2A,} FIG. 20b; _{5-HT 2B,} FIG. 20c; _{5-HT 2C,} FIG. 20d;), histamine H ₁ (H ₁ ) (FIG. 20e), adrenergic α _1A (α _1A ) (FIG. 20f), muscarinic M ₁ (M ₁ ) (FIG. 20g), and dopamine D ₁ (D ₁ ) (FIG. 20h) receptors (A) and (B) are graphs showing G protein dependent signal transduction studies of cyclobenzaprine (circles) and norcyclobenzaprine (triangles).

FIG. 21 shows serotonin (5-HT _2A ) (FIG. 21 d), histamine H ₁ (H ₁ ) (FIG. 21 a), adrenergic α _{1 B} (α _{1 A} ) (FIG. 21 b), which are expressed in human central nervous system. FIG. 21 is a graph showing studies of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to and muscarinic M ₁ (M ₁ ) (FIG. 21 c) receptors. FIG. 21 shows serotonin (5-HT _2A ) (FIG. 21 d), histamine H ₁ (H ₁ ) (FIG. 21 a), adrenergic α _{1 B} (α _{1 A} ) (FIG. 21 b), which are expressed in human central nervous system. FIG. 21 is a graph showing studies of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to and muscarinic M ₁ (M ₁ ) (FIG. 21 c) receptors. FIG. 21 shows serotonin (5-HT _2A ) (FIG. 21 d), histamine H ₁ (H ₁ ) (FIG. 21 a), adrenergic α _{1 B} (α _{1 A} ) (FIG. 21 b), which are expressed in human central nervous system. FIG. 21 is a graph showing studies of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to and muscarinic M ₁ (M ₁ ) (FIG. 21 c) receptors. FIG. 21 shows serotonin (5-HT _2A ) (FIG. 21 d), histamine H ₁ (H ₁ ) (FIG. 21 a), adrenergic α _{1 B} (α _{1 A} ) (FIG. 21 b), which are expressed in human central nervous system. FIG. 21 is a graph showing studies of G protein-independent signaling of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to and muscarinic M ₁ (M ₁ ) (FIG. 21 c) receptors.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. In general, the pharmacology, cell and tissue cultures, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, genetics, and proteins and nucleic acids described herein. The nomenclature used in connection with chemistry and their techniques are well known and commonly used in the art.

  The methods and techniques of the present invention, unless otherwise specified, will be in accordance with the conventional methods known in the art and described in the various general and more specific references cited and discussed throughout this specification. , Generally implemented.

  The chemical terms used herein refer to "The McGraw-Hill Dictionary of Chemical Terms", Parker S. et al. , Ed. McGraw-Hill, San Francisco, C.I. A. As exemplified by (1985), it is used according to the usual usage in the art.

  All of the foregoing and any other publications, patent documents and published patent application documents referenced in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including specific definitions, will control.

  As used herein, variations such as the terms "comprise" or "comprises" or "comprising" refer to the recited integer (or component) or integer (or component) It will be understood to imply to include groups and not exclude any other integers (or components) or groups of integers (or components).

  The singular forms "a", "an" and "the" include plural unless the context clearly dictates otherwise.

  The term "included" is used to mean "including but not limited to". "Including" and "including but not limited to" are used interchangeably.

  "Patient", "subject" or "individual" are used interchangeably and refer to either human or non-human animals. These terms include mammals such as humans, primates, livestock animals (including cows, pigs etc.), pet animals (eg dogs, cats etc.) and rodents (eg mice and rats) .

  "Treatment" of a condition or patient refers to performing steps to obtain beneficial or desired results, including clinical results. Useful or desired clinical results include, but are not limited to, alleviation or alleviation of one or more symptoms associated with the diseases or conditions described herein.

  "Administering" or "administering" a substance, compound or agent to a subject can be performed using one of various methods known to those skilled in the art. For example, the compound or agent can be administered sublingually or intranasally, by inhalation into the lungs, or rectally. Administration can also be performed, for example, once, several times, and / or over one or more time periods. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing the drug. For example, as used herein, a physician who self-administers a drug to a patient or instructs others to administer the drug by a third party and / or prepares a prescription for the drug to a patient may Shall be administered.

  The present invention provides compositions for transmucosal absorption, and methods of administering compounds for transmucosal absorption. The compositions and methods have many surprising pharmacokinetic benefits as compared to oral administration of compounds that absorb the compounds primarily in the stomach, small intestine and colon.

Each of the embodiments described herein can be used individually or in combination with any other embodiments described herein.
Compound

  Compounds useful in embodiments of the present invention include cyclobenzaprine and amitryptyline. In some embodiments, the compound is micronized. In an alternative embodiment, the compound is not micronized. In some embodiments, the compounds may exist in one or more crystalline isoforms.

  As used herein, "cyclobenzaprine" includes cyclobenzaprine and pharmaceutically acceptable salts of cyclobenzaprine (eg, cyclobenzaprine HCl). In some embodiments, cyclobenzaprine can be modified by the covalent attachment of lysine or by conjugation with albumin.

As used herein, "amitriptyline" includes amitriptyline and pharmaceutically acceptable salts of amitriptyline (eg, amitriptyline HCl). In some embodiments, amitriptyline can be modified by the covalent attachment of lysine or by conjugation with albumin.
dose

A "therapeutically effective amount" of a drug or agent, when administered to a subject, has the desired therapeutic effect, eg, reduces the symptoms of fibromyalgia or post-traumatic stress disorder (PTSD), or fibromyalgia Or an amount of a drug or agent that treats the onset of post-traumatic stress disorder (PTSD). The full therapeutic effect does not necessarily occur with the administration of one dose, but may only occur after the administration of a series of doses. In general, treatment with cyclobenzaprine can be performed indefinitely to alleviate the symptoms of interest, and the frequency of administration administered can be varied as needed. Thus, a therapeutically effective amount can be administered in one or more administrations. The exact effective amount necessary for the subject will depend, for example, on the subject's size, health and age, the nature and extent of cognitive impairment, and the treatment or combination of treatments selected for administration, and the method of administration . One of ordinary skill in the art can readily determine the effective amount for a given situation by routine experimentation. Generally, a therapeutically effective amount of cyclobenzaprine or amitriptyline administered to a subject is 0.1 mg to 20.0 mg, 0.1 mg to 5.0 mg, 0.1 mg to 4.0 mg, or 0.1 to 3.0 mg Or 1 to 50 mg, or 1 to 75 mg. In some embodiments, the therapeutically effective amount is about 0.1 mg, 0.5 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1 .7 mg, 1.8 mg, 1.9 mg, 2.0 mg, 2.1 mg, 2.2 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg , 3.0 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4.0 mg, 4.1 mg, 4 .2 mg, 4.3 mg, 4.4 mg, 4.5 mg, 4.6 mg, 4.7 mg, 4.8 mg, 4.9 mg, 5.0 mg, 5.1 mg, 5.2 mg, 5.3 mg, 5.4 mg , 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8 0 mg, 8.5 mg, 9.0 mg, 9.5 mg, 10.0 mg, 12.0 mg, 13.0 mg, 14.0 mg, 15.0 mg, 16.0 mg, 17.0 mg, 18.0 mg, It is 19.0 mg or 20.0 mg. In some embodiments, the therapeutically effective amount is about 21.0 mg, 22.0 mg, 23.0 mg, 24.0 mg, 25.0 mg, 26.0 mg, 27.0 mg, 28.0 mg, 28.0 mg, 29. .0 mg, 30.0 mg, 31.0 mg, 32.0 mg, 34.0 mg, 35.0 mg, 36.0 mg, 37.0 mg, 38.0 mg, 39.0 mg, 40.0 mg, 41.0 mg , 43.0 mg, 44.0 mg, 45.0 mg, 46.0 mg, 47.0 mg, 48.0 mg, 49.0 mg, or 50.0 mg. In some embodiments, amtriptyline is present in the compositions of the invention in an amount of 1 mg to 25 mg, such as 1 mg to 10 mg. In certain embodiments, amitriptyline is present in an amount of less than about 8 mg, less than about 16 mg, about 16 mg, or about 24 mg.
Administration

  A suitable method of administering a substance, compound or drug to a subject is, for example, the age of the subject, whether the subject is active or inactive at the time of administration, or whether the subject is experiencing symptoms of a disease or condition at the time of administration. It will depend on the extent of the condition and the chemical and biological properties (eg, solubility, digestibility, bioavailability, stability and toxicity) of the compound or agent. In some embodiments, the compound is administered for transmucosal absorption. The absorption properties of the compounds of the invention by transmucosal delivery can not be predicted without experimental methods. The suitability of the compounds of the invention for transmucosal absorption is a surprising feature. Transmucosal absorption can occur through any mucous membrane. Exemplary mucosas include oral mucosa (eg, buccal and sublingual mucosa), nasal mucosa, rectal mucosa, and lung mucosa. In some embodiments, the composition is suitable for transmucosal absorption. In some embodiments, the composition is formulated for transmucosal absorption.

  Methods of administering compositions for transmucosal absorption are well known in the art. For example, the composition can be administered by buccal tablets, lozenges, buccal tablets, and buccal spray solutions for buccal absorption. The composition can be administered by sublingual tablet, sublingual film, liquid, sublingual powder and sublingual spray solution for sublingual absorption. The composition can be administered by nasal spray for intranasal absorption. The composition can be administered by aerosolized composition or inhalable dry powder for pulmonary absorption. The composition can be prepared as a solution using saline when administered by a spray or aerosolized composition, and may use benzyl alcohol or other suitable preservatives, or enhance bioavailability Promoter, fluorocarbon and / or other solubilizers or dispersants can be included.

Dosages and dosing regimens can be determined by one of ordinary skill in the art, as needed for the subject being treated. The skilled artisan can consider such factors as the age or weight of the subject, the severity of the disease or condition undergoing treatment, and the subject's response to treatment. The compositions of the invention can be administered, for example, on an as-needed basis or on a once-a-day basis. In some embodiments, the composition can be administered immediately before sleep or several hours before sleep. Pre-sleep administration can be beneficial by providing a therapeutic effect before the onset of symptoms of the disease or condition being treated. Administration can be performed over various periods of time. For example, the dosing regimen should be continued for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more weeks. Can. In some embodiments, the dosing regimen is one, two, three, four, five, six, seven, eight, nine, ten months. Continue for 11 months, 12 months, or more.
Use for treatment

The compounds of the present invention can be used to treat or prevent the onset of fibromyalgia syndrome, also known as conjunctivitis (eg, Moldofsky et al., J Rheumatol
38 (12): 2653-2663 (2011) and Thomas, J. Rheumatol 38 (12): 2499-2500 (2011)). Fibromyalgia is a chronic non-inflammatory rheumatic disorder. The American College of Rheumatology (ACR) published a classification criteria for fibromyalgia in 1990 (Wolfe, F. et al., Arthritis)
and Rheumatism 33: 160-172 (1990)). Subsequently, a revised version of the ACR standard was published (Wolfe et al., J Rheumatol 38 (6): 1113-22 (2011)). Diagnostic criteria were published by the "Outcome Measures in Rheumatology" clinical trial or an international network of working groups called OMERACT (Mease P et al., J Rheumatol. 2009; 36 (10): 2318-29). Fibromyalgia is conventionally characterized by stiff or diffused pain, aching pain, muscle soreness, sleep disturbance, or fatigue. Pain is generally pervasive, but is generally localized to a specific "torting point" that can lead to extensive pain and muscle spasm when contacted. Other symptoms include mental and emotional disturbances such as reduced concentration and irritability, neuropsychiatric symptoms such as depression and anxiety, joint swelling, headache, numbness. Fibromyalgia is associated with cognitive impairment including non-refreshable sleep, fatigue, drowsiness, regurgitation, mental haze, and difficulty working in parallel. Fibromyalgia also often co-exists sleep disorder, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the present invention can be used to treat any one of the conditions identified above and any combination thereof.

  According to one physician, fibromyalgia is further divided into two categories: primary fibromyalgia or secondary-associated fibromyalgia. In general, primary fibromyalgia syndrome can be regarded as fibromyalgia occurring in the absence of another serious condition, while secondary-consistent fibromyalgia is another serious medicine. Can be regarded as fibromyalgia occurring in the presence of a sexual disorder, these other disorders may be caused by the patient's fibromyalgia or simply related to the patient's fibromyalgia doing. For secondary or concomitant fibromyalgia, classical or limited rheumatoid arthritis, knee or hand osteoarthritis of the knee or hand, lower back pain syndrome, cervical pain syndrome, cancer pain syndrome, temporomandibular joint disorder Fibromyalgia in patients with migraine headache, menopause, post-traumatic stress disorder, and interstitial cystitis or painful bladder syndrome (or a combination thereof) may be included.

  The compounds of the invention can also be used to treat or prevent the onset (either onset, consolidation or persistence) of PTSD symptoms following a traumatic event. Trauma events are actual personal deaths or direct personal experiences with serious injuries or their threats, or other threats to the physical integrity of the individual, or death, injury or physical integrity of another person. Sighting of events with threats; or defined as knowing about unexpected or violent death, serious harm, or threat of death or injury experienced by a member of the family or other close relatives. Directly experienced trauma events include combat, violent personal attacks (sexual assaults, physical assaults, robbery, street robbers), abduction experiences, hostage experiences, terrorist raids, torture, war prisoners of war or This includes, but is not limited to, the diagnosis of imprisonment in concentration camps, natural or human disasters, serious motor vehicle accidents, or life-threatening diseases. For children, sexual trauma events may include developmentally inappropriate sexual experiences that do not involve actual violence or injury or their threats. Eye sightings include looking at another person's serious injury or unnatural death resulting from a violent attack, accident, war or disaster, or unexpectedly witnessing a corpse or part of a corpse But not limited to. The events experienced by others who have come to know know violent personal attacks experienced by family members or close friends, serious accidents or serious injuries, and unexpected sudden death of family members or close friends, or It can include, but is not limited to, knowing that your child has a life-threatening disease. The disorder may be particularly serious or last long, especially if the stressor is due to a human conspiracy (eg, torture or rape). The onset of PTSD symptoms typically occurs shortly after the traumatic event, but PTSD symptoms also appear during the traumatic event and become increasingly serious. One theory of how PTSD develops is that there is a type of "learning" or reinforcement process in which trauma memory is deeply rooted in the mind. As these memories become more fixed (a process called consolidation), symptoms such as flashback and nightmares become more severe and frequent. Intervention at this very important time can prevent some patients from developing full-fledged PTSD. Enhancement of PTSD symptoms typically occurs during weeks and months after trauma events. Human memory for trauma events becomes enhanced to very vivid and clear memories, which are re-experienced frequently as either flashbacks or nightmares. At this time, hyperarousal symptoms and avoidance behavior may become increasingly serious and may cause problems in daily life. Persistence of PTSD symptoms occurs when the memory of trauma is enhanced, and re-experience symptoms (flashback and nightmares) and hyper-arousal symptoms become persistent and levels that functionally interfere with the patient's daily life Stay in

  The compositions and methods of the present invention can be used at various time intervals to treat different phases of PTSD development following a traumatic event. For example, to treat the onset phase of PTSD, it may be necessary to administer the composition of the invention shortly after the trauma event, eg within one week, within two weeks, within three weeks, or within four weeks or later. May be On the other hand, when treating the enhanced phase of PTSD, the person skilled in the art will recognize that some time after the trauma event, some time during onset of symptoms, for example within 1 month, 2 months, or 3 months or later. It may be possible to administer the composition of the invention. The permanence phase of PTSD can be treated with a composition of the invention administered three months or more after trauma events, eg, within three months, four months, five months or more. PTSD symptoms are alleviated or eliminated as a result of treatment in the initiation, consolidation, or persistence phase.

  The compositions and methods of the invention can also be used to treat traumatic brain injury (TBI). TBI is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the invention can also be used to treat any of the foregoing conditions in combination with, or independently of, treatment of TBI.

  The compositions and methods of the invention can also be used to treat chronic traumatic encephalopathy (CTE). CTE is associated with sleep disorders, sleep disturbances, fatigue, non-restorative sleep, anxiety and depression. The compositions and methods of the present invention can also be used to treat any of the foregoing conditions, either in combination with or independently of the treatment of CTE.

The compositions and methods of the invention can be used to treat sleep disorders or disturbances of sleep. "Sleep disorder" can be any one of four major categories of sleep dysfunction (DSM-IV, pages 551-607; The International Classification of Sleep Disorders: (ICSD) Diagnostic and Coding Manual, 1990 (See also American Sleep Disorders Association). One category, primary sleep disorders, includes sleep disorders not arising from another mental disorder, substance, or general medical condition. This sleep disorder includes primary insomnia, primary hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, night awakening disorder, ambush disorder, rem sleep behavior disorder, sleep paralysis, day-night reversal and other Related disorders; substance-induced sleep disorders; and sleep disorders resulting from general medical conditions include, but are not limited to. Nonrestorative sleep, which is primary insomnia, has been described by DSM-IV-TR as a type of primary insomnia, the main problem in this case is that it has not been refreshed or refreshed on waking up Feel that The second category includes sleep disorders caused by substances including drugs and drugs of abuse. The third category includes sleep disturbances resulting from the action of general medical conditions on the sleep / wake system. The fourth category of sleep disorders includes sleep disorders that result from identifiable mental disorders such as mood or anxiety disorders. The fifth category of sleep disorders includes sleep disorders described as non-recoverable sleep. One definition of non-restoring sleep is described in the DSM-IV-TR as a type of primary insomnia (A1.3), the main problem in this case is that it has not been refreshed on wake up, or I feel that I could not refresh. Symptoms of each category of sleep disorder are known in the art. "Disruption of sleep" may be a dysfunction in sleep that can be refreshed. Such a clinical diagnosis can be made based on the patient's own description of awakening fatigue sensation or the patient's report of poor sleep. Such a good sleep disturbance can be described as shallow sleep or frequent awakening, which is an increase in cyclic alternation pattern (CAP) A2 or A3 rate or cycle duration, or CAP in non-REM sleep (A2 + A3) Increase of normalized CAP A2 + A3 as determined by A / CAP (A1 + A2 + A3) (e.g., Moldofsky et al., J. Rheumatol 38 (12): 2653-2663 (2011) and Thomas, J Rheumatol 38 (12)) (See, eg, pages 2499-2500 (2011)), it may be related to alpha rhythm contamination in non-REM sleep, or the absence of physically-increasing delta waves during deeper sleep. Such "sleep disturbance" may or may not rise to the level of "sleep injury" as defined in DSM-IV, but these sleep disturbances are common to one Or you may share multiple symptoms. Symptoms of sleep disturbance are known in the art. Known symptoms include a feeling of drowsy or vague, feeling of tiredness, feeling of tiredness, and difficulty concentrating during awakening. Sleep related conditions that can be treated with the methods and compositions of the invention include sleep disorders (eg intrinsic sleep disorders such as sleep misidentification, psychopsychotic insomnia, idiopathic insomnia, obstructive sleep) Apnea syndrome, central sleep apnea syndrome, central alveolar hypoventilation syndrome, restless leg syndrome, and periodic limb movement disorder; exogenous sleep disorder such as environmental sleep disorder, adaptive sleep disorder, lack of discipline (Limit-setting) sleep disorder, stimulant dependent sleep disorder, alcohol dependent sleep disorder, toxin-induced sleep disorder, sleep onset related disorder, sleep agent dependent sleep disorder, inappropriate sleep hygiene, high altitude insomnia, sleep deprivation Syndrome, nocturnal feeding syndrome, and nocturnal drinking syndrome; and circadian rhythm sleep disorders such as jet lag syndrome, sleep phase regression syndrome, sleep phase progression syndrome, shift work Sleep disorder, non-24 hour sleep-wake disorder, and irregular sleep-wake pattern), sleep-related disorder (eg wake disorder such as dreaming sickness, confusional awakening, and night startle and sleep-wake transition disorder such as Included are dyskinesias, sleep talks and sleep starts, and nocturnal leg cramps), and sleep disorders associated with medical or psychiatric conditions or disorders.
Basifying agent

The compositions of the present invention can include basifying agents in addition to the compounds useful in the compositions of the present invention. As used herein, "basicizing agents" are agents that raise the pH of a solution containing a compound (eg, cyclobenzaprine HCl or amitriptyline HCl) useful in the compositions and methods of the invention. (Eg, potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH ₂ PO ₄ ), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, K ₂ HPO ₄ ), tripotassium phosphate (K ₃ PO ₄ ), sodium dihydrogen phosphate (monosodium phosphate monobasic sodium phosphate, NaH ₂ PO ₄ ), disodium hydrogen phosphate (disodium phosphate disodium phosphate) sodium phosphate _monobasic, Na 2 _HPO 4), trisodium phosphate _(Na 3 _PO 4), bicarbonate or carbonate, citric acid dipotassium Tripotassium citrate, disodium citrate, trisodium citrate, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugated bases of some organic acids (including bicarbonates), and Substances that increase the local pH of liquids near mucosal surfaces, including sulfides). The solution of interest is a layer of aqueous material that covers the mucous membrane. Thus, the basifying agent is sometimes one component (and excipient) in the tablet, and the basifying agent exerts its effect while the tablet is being dispersed in the mucosal material, while part of the formulation is Dissolved in the mucosal material for a certain period of time after the tablet dissolves in the mucosal material. Surprisingly, the pharmacokinetic properties of the composition are improved by adding a basifying agent to the composition of the invention. This is exemplified by cyclobenzaprine HCl as one particular compound useful in the methods and compositions of the present invention. A basifying agent having a particular effect on cyclobenzaprine HCl is dipotassium hydrogen phosphate (K ₂ HPO ₄ ). Another basifying agent with particular effect on cyclobenzaprine HCl is potassium dihydrogen phosphate (KH ₂ PO ₄ ). Another basifying agent with particular effect on cyclobenzaprine HCl is disodium hydrogen phosphate (Na ₂ HPO ₄ ). Another basifying agent with particular effect on cyclobenzaprine HCl is tripotassium citrate. Another basifying agent with particular effect on cyclobenzaprine HCl is trisodium citrate. In some embodiments, amitriptyline HCl is a specific compound useful in the methods and compositions of the present invention. Basifying agents having a specific effect on amitriptyline HCl _is K 2 HPO _4. Another basifying agent with a specific effect on amitryptiline HCl is Na ₂ HPO ₄ . Another basifying agent with particular effect on amitriptyline HCl is KH ₂ PO ₄ . Another basifying agent that has a particular effect on amitriptyline HCl is tripotassium citrate. Another basifying agent with particular effect on amitryptiline HCl is trisodium citrate.

Cyclobenzaprine HCl has an acid dissociation constant (or pKa) of the amine group of approximately 8.5 at 25 ° C., which means that the compound is 50% ionized or protonated at pH 8.5 (50% non-ionized or free base) (M. L. Cotton, G. R. B. Down, Anal. Profiles Drug
Subs. 17, pp. 41-72 (1988)). The pH of 10 gm / 100 mL (0.32 mol) to 30 gm / 100 mL (0.96 mol) of aqueous solution of cyclobenzaprine HCl is approximately 3.1 to 3.3, whereby almost all of the cyclobenzaprine is ionized And the state of becoming soluble is provided. Thus, one skilled in the art who has this knowledge can be careful to maintain cyclobenzaprine at a low pH and maximize its solubility. However, ionized cyclobenzaprine may not be optimally absorbed through mucosal surfaces due to its charge. This problem is solved by combining cyclobenzaprine with a basifying agent. Indeed, when we combine cyclobenzaprine HCl with a basifying agent such as dipotassium hydrogen phosphate (K ₂ HPO ₄ ) or potassium dihydrogen phosphate (KH ₂ PO ₄ ), cyclobenzaprine is It has been found that the pharmacokinetic properties of the composition for transmucosal absorption, including For experiments with oral and intravenous solutions containing cyclobenzaprine and a basifying agent, the pH was adjusted to about pH 7.1 to pH 7.4. In experiments with tablet formulations containing cyclobenzaprine and a basifying agent, the addition of the basifying agent results in a higher pH when the tablet is dissolved in water. Also, the combination of cyclobenzaprine with a basifying agent enhances the uptake of cyclobenzaprine by transmucosal absorption. The 2.5 mg / ml cyclobenzaprine HCl solution in 7.4 containing K ₂ HPO ₄ or KH ₂ PO ₄ is probably because the concentration of cyclobenzaprine free base is increased compared to ionized cyclobenzaprine K ₂ HPO ₄ or KH ₂ for transmucosal pharmacokinetic properties of compositions containing cyclobenzaprine since it is near its saturation point where cyclobenzaprine is likely to be extracted from solution or become insoluble. The effect of basifying agents such as PO ₄ is significant. Without being bound by any theory, basifying agents may increase the pH of the microenvironment local to the mucosa, causing more cyclobenzaprine to become non-ionized or free base at the mucosal surface It is possible that it helps cyclobenzaprine to enter the bloodstream via the mucous membrane, thereby reducing any solubility of cyclobenzaprine resulting from the action of the basifying agent in solution near the mucous membrane Be offset. Without being bound by any theory, the basifying agent can create a transition state involving hydration of the free base, so that the free base is formed in situ near the mucosal surface to pass.

The basifying agents useful in the compositions and methods of the present invention may be any agent that increases the pH of the solution containing the compounds that is useful in the methods and compositions of the present invention. Exemplary basifying agents include potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KH ₂ PO ₄ ), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic phosphate) Potassium, K ₂ HPO ₄ ), tripotassium phosphate (K ₃ PO ₄ ), sodium dihydrogenphosphate (monosodium phosphate, monobasic sodium phosphate, NaH ₂ PO ₄ ), disodium hydrogenphosphate (phosphorus) Disodium acid, dibasic sodium phosphate, Na ₂ HPO ₄ ), trisodium phosphate (Na ₃ PO ₄ ), sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, potassium carbonate, sodium bicarbonate Included are potassium carbonate, potassium acetate, sodium acetate, potassium citrate and sodium citrate. In some embodiments, the composition of the present invention has a molar ratio of the compound (eg, cyclobenzaprine or amitryptyline) to the basifying agent is 1: 1, 1: 2, 1: 3, 1: 4, 1: 5 1: 6, 1.7, 1.8, 1.9 or 2.0. In some embodiments, the ratio of cyclobenzaprine HCl (2.4 mg, MW 275.387) to K ₂ HPO ₄ (1.05 mg, MW 174.2) is 0.69.
Metabolism of cyclobenzaprine and amitriptyline

Cyclobenzaprine is rapidly distributed from the vasculature after an intravenous (IV) bolus administration to humans (Hucker et al., J Clin Pharmacol 17: 719-727 (1977), Hucker et al., Drug Metab Dispos 6: 659-672 (1978), Till et al., Annu Rev Pharmacol Toxicol 40: 581-616 (2000), and Winchell et al., J Clin Pharmacol 42: 61-69 (2002). ). The amount of cyclobenzaprine in plasma within 3 to 30 minutes was less than 5% of the theoretical initial concentration (C _init ) of each injected dose, and at 3 minutes a relatively high C _init resulted. Overall, this information indicates that cyclobenzaprine is rapidly distributed from plasma. As more than 95% of the injected cyclobenzaprine is excluded from plasma prior to the first time point of any of the four previously listed studies, these studies It does not provide information on the half-life of one phase and remains to define that the upper limit of the half-life of the first phase is clearly less than 3-5 minutes.

  Amitriptyline is structurally related to cyclobenzaprine but differs chemically from cyclobenzaprine by the absence of the C10-C11 double bond of the central cycloheptyl ring. However, changes in chemical structure can affect drug action on normal or pathological tissues, as well as absorption, disposal, metabolism and excretion. Amitriptyline and its demethylated metabolite nortriptyline are pharmaceutically active ingredients of the tricyclic antidepressants (TCAs) Elavil® and Pamelor®, respectively. Amitriptyline, like cyclobenzaprine, is rapidly distributed from plasma. The pharmacokinetics of IV administration of cyclobenzaprine or amitriptyline, or IV administration of amitriptyline, can be described by a two-compartment model containing a plasma "central" compartment and a "peripheral" compartment.

  Neither cyclobenzaprine nor amitriptyline is useful for the long-term treatment of fibromyalgia in any of the formulations tested, for example, the currently available formulations were not effective for 6 months of treatment (Carette, S Arthritis Rheum. 1994, January; 37 (No. 1): 32-40). Cyclobenzaprine is not effective for treatment of fibromyalgia in a 12 week study (Bennett et al., Arthritis Rheum. 31: 1535-1542 (1988)). In general, cyclobenzaprine is not recommended for long-term use. We hypothesized that fatigue, somnolence and epilepsy sensory side effects outweigh the treatment effect with cyclobenzaprine or amitryptiline, but shorten the plasma half-life of either cyclobenzaprine or amitryptiline The method to do this was not known. Furthermore, the inventors have shown for the first time that the ineffectiveness of cyclobenzaprine may be due to the metabolism of cyclobenzaprine by the liver. Amitriptyline is known to be metabolized to nortriptyline, and delayed plasma half-life of nortriptyline has been reported (Bhatt, Biomed Chromatogr 24 (11): 1247-54 (2010)) but nortriptyline accumulation. However, a scheme that could reduce the efficiency of amitriptyline at bedtime as a long-term treatment was not understood.

  Cyclobenzaprine is extensively metabolized and excreted as an N + -glucuronide conjugate primarily by the kidney in humans. Glucuronidation of aliphatic tertiary amine groups in the molecule results in quaternary ammonium linked glucuronide metabolites (ie N + -glucuronides) (Hucker et al., Drug Metab Dispos 6: 659-672 (1978) Hawes, Drug Metab Dispos 26: 830-837 (1998)). Amitriptyline has recently been studied in more detail than cyclobenzaprine, and the enzyme UDP-glucuronysl-transferase (UGT) UGT2B10 has been found to be a high affinity component ( Zhou et al., Drug Metab Dispos 38: 863-870 (2010), UGT1A4 is a low affinity enzyme for glucuronidation in human liver microsomes (HLM) (Breyer-Pfaff et al., Drug Metab Dispos 25). : 340-345 (1997), Nakajima et al., Drug Metab Dispos 30: 636-642 (2002)). Similarly, cyclobenzaprine is metabolized to cyclobenzaprine-N + -glucuronide by UGT2B10, but likely to be less metabolized by UGT1A4.

  In addition, cyclobenzaprine is N-substituted with 3- (5H-dibenzo [a, d] cyclohepten-5-ylidene) -N-methyl-1-propanamine (norcyclobenzaprine) mainly by hepatic enzymes P450 3A4 and 1A2. -Demethylated (Wong et al., J Anal Toxicol 19: 218-224 (1995)). Amitriptyline is likewise subjected to P450-mediated N-demethylation to nortriptyline. While nortriptyline results in a significant percentage of plasma amitriptyline and nortriptyline content in subjects receiving amitriptyline as a single dose or on a long-term basis, norcyclobenzaprine is present in human plasma, except in the case of overdose. Not measured (Hucker et al., Drug Metab Dispos 6: 659-672 (1978), Wong et al., J Anal Toxicol 19: 218-224 (1995)).

Heretofore, several studies have been performed and published showing that cyclobenzaprine, amitriptyline and nortriptyline bind to various receptors in the central nervous system and peripheral tissues. We performed a systematic analysis of the binding affinities of these molecules (cyclobenzaprine, amitriptyline and nortriptyline) and the binding affinities of norcyclobenzaprine (before we gain knowledge) Was not studied at all), we determined the K _{i of} these molecules for various receptors. The binding of cyclobenzaprine, norcyclobenzaprine, amitryptyline and nortriptyline to the receptor was studied by the following method: Adrenergic alpha-2A (Langin et al., Eur J Pharmacol 167: 95-104 (1989) Year), -2B and -2C receptors (Devdejian et al., Eur J Pharmacol 252: 43-49 (1994)), histamine H1 receptor (Smit et al., Brit. J. Pharmacol 117: 1071-1080). (1996)), muscarinic M1 and M2 receptors (Dorje et al., J Pharmacol Exp Ther 256: 727-733 (1991)), and 5-HT1A (Mulheron et al., J
Biol Chem 269: 12954-12962 (1994), 5-HT2A (Bonhaus et al., Brit J Pharmacol 115: 622-628 (1995)) and 5-HT2C receptor (Stam et al., Eur J Pharmacol). 269: 339-348 (1994)). The binding constants K _i are listed in Table 1 below. Cyclobenzaprine and norcyclobenzaprine exhibited high affinity binding (K _i ) to the following receptors in vitro: 5HT 2a (5.2 nM and 13 nM) and 5HT 2 c (5.2 nM and 43 nM, respectively) , Alpha-adrenergic alpha-1 A (5.6 nM and 34 nM), alpha-2B (K _i = 21 nM and 150 nM) and alpha-2 C (K _i = 21 nM and 48 nM); H1 (1.3 nM and 5.6 nM) And M1 (7.9 nM and 30 nM). Norcyclobenzaprine, like cyclobenzaprine, becomes a functional antagonist to 5HT2a by Ca ⁺ mobilization (IC ₅₀ = 92 nM). Cyclobenzaprine is also an antagonist to 5HT2b (IC ₅₀ = 100 nM). Cyclobenzaprine and norcyclobenzaprine are functional antagonists to 5HT2c (IC ₅₀ = 0.44 μM and 1.22 μM) and alpha-2A (IC ₅₀ = 4.3 μM and 6.4 μM). In contrast, both cyclobenzaprine and norcyclobenzaprine are functional agonists for 5HT1a (EC ₅₀ = 5.3 μM and 3.2 μM). The antagonist activity of cyclobenzaprine for 5HT2b is consistent with its lack of association with cardiac valve pathology. Antagonists of 5HT2a and H-1 are known to have effects on sleep and sleep maintenance. Adrenergic antagonists can have an effect on autonomic dysfunction.

Without being bound by any theory, we believe that the main activity of cyclobenzaprine for its effects on fibromyalgia, PTSD, TBI and sleep disturbance is binding to 5-HT2a. Assume. Plasma cyclobenzaprine and norcyclobenzaprine were measured over 168 hours in 10 fasted, healthy subjects who received 5 mg of oral (PO) immediate release cyclobenzaprine HCl. The oral bioavailability of cyclobenzaprine was similar to the published results (C _max = 4.12 ng · mL ⁻¹ , t _max = 3.5 h, AUC _0−∞ = 103.1 ng · hr • mL ⁻¹ ), plasma norcyclobenzaprine was unexpectedly high and persistent (C _max = 1.27 ng · mL ⁻¹ , t _max = 24.0 hours, AUC _{0 −} = = 169. 5 ng · hr · mL ⁻¹ ). We first calculated the half-life of norcyclobenzaprine in human plasma after oral ingestion of 5 mg cyclobenzaprine HCl immediate release tablet (72.8 hours), which is the cyclobenza in the same study It is significantly longer than the half life of purines (31.0 hours).

薬物動態特性 Not to be bound by any theory, the inventors have long stated that the therapeutic goal is to dynamically alter cyclobenzaprine levels over the course of a day, for bedtime or once-a-day use It is assumed that the efficiency of cyclobenzaprine treatment over time is impeded by the accumulation of norcyclobenzaprine. Accumulation of biologically active norcyclobenzaprine may influence the response to treatment with cyclobenzaprine in long-term dosing regimens at bedtime. Without being bound by any theory, we can adapt various mechanisms to control neuronal signaling flexibility and responsiveness by long-term occupancy of 5-HT2A and other receptors Suppose. The present inventors have, nor cyclobenzaprine has a 13.2nM _{K i} of relative 5-HT2a, cyclobenzaprine is has been found to have a _{K i} of 5.1nM against 5HT2A This indicates that norcyclobenzaprine competes with cyclobenzaprine for binding to 5-HT2A. Similarly, nortriptyline has a _{K i} of 16nM against 5-HT2A, amitriptyline, has a _{K i} of 2.5nM against 5-HT2A, this is, nortriptyline is 5- It is shown to compete with amitryptyline for binding to HT2A. Cyclobenzaprine and amitriptyline are 5-HT2A binders with higher avidity than norcyclobenzaprine and nortriptyline, but the concentrations of norcyclobenzaprine and nortriptyline are particularly good for continuous dosing regimens of once daily dosing schedule Due to the longer half life and accumulation, it is significantly higher. By administering cyclobenzaprine or amitriptyline for transmucosal absorption, cyclobenzaprine or amitriptyline avoids first-pass metabolism in the liver, thereby norcyclobenzaprine by intestinal and hepatic p450 metabolism, respectively The formation of nortriptyline is reduced or eliminated. Thus, cyclobenzaprine and amitriptyline can be effectively administered without accumulation of demethylated metabolites over a therapeutic regimen longer than currently possible therapeutic regimens. Without being bound by any theory, the inventors have found that the long half-lives of norcyclobenzaprine and nortriptyline are due to the instability of norcyclobenzaprine-N + -glucuronide and nortriptyline (Nortriptyline (Nortriptyline). The inventors observed in an attempt to synthesize cyclobenzaprine-N + -glucuronide), and presumably human enzymes comprising UDP-glucuronosyltransferase (UGT) UGT2B10 and UGT1A4 can be excreted in the kidney -N + -glucuronide metabolite It is assumed that it is because it can not form. Norcyclobenzaprine has not been measured in animal plasma after administration for treatment, and the long half-life of norcyclobenzaprine has not been known so far, norcyclobenzaprine has been identified in CNS and peripheral tissues. The benefit of transmucosal administration to reduce norcyclobenzaprine and increase the potential therapeutic potential of cyclobenzaprine is surprising, as it is known not to bind to 5-HT2A or other receptors in And was new. In contrast, the half-life of nortriptyline after ingestion of either amitriptyline or nortriptyline is known to be long, and the long half-life of nortriptyline in the plasma and at the site of action treat depression and major depressive disorder Seems to be an advantage of
Table 1: Binding affinity of cyclobenzaprine, norcyclobenzaprine, amitryptyline and nortriptyline for various receptors

Pharmacokinetic characteristics

Transmucosal absorption of compounds useful in the compositions and methods of the present invention has many beneficial effects on the pharmacokinetic properties of the compounds, in addition to the benefit of avoiding formation of norcyclobenzaprine. Transmucosal delivery causes the compounds of the present invention to be absorbed more rapidly than when administered orally, resulting in a shorter time to reach therapeutic concentrations of cyclobenzaprine or amitryptiline in plasma. In some embodiments, compositions of the present invention provide therapeutic concentrations of cyclobenzaprine or amitryptiline in plasma less than 3.3 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1 hour , Less than 45 minutes, less than 30 minutes, or less than 20 minutes. In some embodiments, the compositions of the present invention allow high concentrations of cyclobenzaprine or amitryptiline in plasma to be within 3.3 hours, 3 hours, 2.5 hours, as compared to oral administration. Obtained within 2 hours, 1 hour, 45 minutes, 30 minutes or 20 minutes. In some embodiments, the compositions of the present invention have a high AUC of cyclobenzaprine or amitryptiline in plasma as compared to oral administration, from 0 to 3.3 hours, 0 to 3 hours, 0 to 2. Obtained in 5 hours, 0-2 hours, 0-1 hours, 0-45 minutes, 0-30 minutes, or 0-20 minutes. In some embodiments, the compositions of the invention allow high dose normalized concentrations (dnC ^* ) of cyclobenzaprine or amitriptyline in plasma compared to oral administration within 3.3 hours, 3 hours or less Within 2.5 hours, within 2 hours, within 1 hour, within 45 minutes, within 30 minutes, or within 20 minutes. In some embodiments, the compositions of the present invention allow high dose normalized AUC (dnAUC ^* ) of cyclobenzaprine or amitryptiline in plasma to be 0 to 3.3 hours, 0 to 3.3 hours, as compared to oral administration. Obtained in 3 hours, 0 to 2.5 hours, 0 to 2 hours, 0 to 1 hours, 0 to 45 minutes, 0 to 30 minutes, or 0 to 20 minutes. Transmucosal delivery causes the compounds of the present invention to be absorbed more rapidly than when administered orally, resulting in shorter times to reach maximal concentrations or _tmax . In some embodiments, the composition of the invention is less than 5 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, 1 hour Less than 45 minutes, less than 30 minutes, less than 15 minutes, less than 10 minutes, or less than 5 minutes resulting in a t _max of cyclobenzaprine or amitryptiline. In some embodiments, the composition of the present invention comprises about 5 hours, about 4 hours, about 3 hours, about 2.5 hours, about 2 hours, about 1.5 hours, about 1 hour, about 45 minutes, Provides a t _max of cyclobenzaprine or amitryptyline for about 30 minutes, about 15 minutes, about 10 minutes, or about 5 minutes.

Transmucosal absorption also results in higher plasma concentrations of the compound as compared to oral administration. The plasma concentration may be an individual plasma concentration or an average plasma concentration when observing a plurality of individuals. The higher plasma concentration obtained by transmucosal absorption can be determined by measuring the plasma concentration of the administered compound, or by calculating the ratio of plasma concentration to the administered dose, which is dose normal. Plasma concentration (C) or dnC ^* , measured in mL- ¹ . dnC ^* is calculated by determining the ratio of plasma levels to the dose administered. For example, when 2.4 mg of cyclobenzaprine or amitriptyline is administered and the plasma level is 2.4 ng / mL at 3 hours, dnC ^{* at} 3 hours is ((2.4 ng / mL) / (2.4 mg) ) = 1.0 x 10 ^-6 mL ^-1 . dnC ^* can be measured at either a fixed or variable time point, for example at a time point corresponding to C _max . The dose normalized concentration of cyclobenzaprine in plasma after taking 5 mg of immediate release cyclobenzaprine, ie, dnC ^* of cyclobenzaprine is 0.00 at 20 minutes and 1.95 × 10 ^{− at} 30 minutes. ⁹ mL ^-1 , 19.31 x 10 ^-9 mL ^-1 in 45 minutes, 50.00 x 10 ^-9 mL ^-1 in ¹ hour, 378.65 x 10 ^-9 mL in 2 hours is ^-1, in 2.5 hours (150 minutes) and 510.94 × ¹⁰ -9 ^mL-1, a ^{625.29 × 10 -9 mL -1 × 10} -9 mL -1 at 3 hours, in 3.3 hours (200 minutes) and 698.49 × ¹⁰ -9 ^{mL -1,} it was 818.31 × ¹⁰ -9 ^{mL -1} in 3.67 hours (220 minutes), 8 at 4 hours 8.33 × ¹⁰ a -9 ^{mL -1,} it was 968.09 × ¹⁰ -9 ^{mL -1} in 4.33 hours (260 minutes), 933.95 × 10 in 4.67 hours (280 minutes) ^- a ⁹ mL ^-1, was 932.86 × ¹⁰ -9 ^{mL -1} in 5 hours, a 920.94 × ¹⁰ -9 ^{mL -1} in 5.5 hours (330 minutes), 953 in 6 hours. 40 × 10 ⁻⁹ mL ⁻¹ , 81.2 hours at 801.23 × 10 ⁻⁹ mL ⁻¹ , 12 hours at 516.73 × 10 ⁻⁹ mL ⁻¹ , 16 hours at 347.39 × 10 ⁹ mL ⁻¹ 10 is ^-9 mL ^-1, was 320.44 × ¹⁰ -9 ^{mL -1} in 24 hours, at 36 hours is ^{233.66 × 10 -9 mL -1, 199.41} × 10 in 48 hours ^- a mL ^-1, was 136.80 at 72 hours. The dose-normalized concentration of cyclobenzaprine in the plasma after ingestion of 2.4 mg sublingual cyclobenzaprine and phosphate, ie, dnC ^* of cyclobenzaprine, is 157.60 × 10 ^-9 mL ^-1 at 20 minutes. There is 301.60 × ¹⁰ -9 ^{mL -1} in 30 minutes, is 432.58 × ¹⁰ -9 ^{mL -1} in 45 minutes, is 598.85 × ¹⁰ -9 ^{mL -1} in 1 hour, in 2 hours is 683.58 × ¹⁰ -9 ^{mL -1,} in 2.5 hours (150 minutes) and ^{727.67 × 10 -9 mL -1, 840.33} × 10 -9 mL in 3 hours ^- a ¹ × ¹⁰ -9 ^{mL -1,} was 923.58 × ¹⁰ -9 ^{mL -1} in 3.3 hours (200 minutes), in 3.67 hours (220 minutes) 952.7 × ¹⁰ a -9 ^{mL -1,} was 1,012.35 × ¹⁰ -9 ^{mL -1} in 4 hours, a 1,030.10 × ¹⁰ -9 ^{mL -1} in 4.33 hours (260 minutes), 4. in 67 hours (280 minutes) was 1038.58 × ¹⁰ -9 ^{mL -1,} was 990.90 × ¹⁰ -9 ^{mL -1} in 5 hours, 1,046.42 × 10 in 5.5 hours (330 minutes) ⁻⁹ mL ⁻¹ , and 6 hours at 911.07 × 10 ⁻⁹ mL ⁻¹ , 8 hours at 696.33 × 10 ⁻⁹ mL ⁻¹ , and 12 hours at 504.90 × 10 ^−9. mL is ^-1, in 16 hours was 354.04 × ¹⁰ -9 ^{mL -1,} was 294.40 × ¹⁰ -9 ^{mL -1} in 24 hours, 184.19 × ^{10 -9} at 36 hours An L ^-1, is 143.37 × ¹⁰ -9 ^{mL -1} in 48 hours was 88.23 in 72 hours. For example, dnC ^* is 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 20 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration After 2 hours, 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration It can be measured after, 11 hours after administration, or 12 hours after administration. For example, the dnC ^* value is about 8.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 0.001 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 0.01 ± 25% × 10 ⁻⁶ mL ^{− 1} , about 0.05 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 0.1 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 0.5 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 1. 0 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 5.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 10.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 50.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or about 100.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 125.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , about 150.0 ± 25% × 10 ⁻⁶ mL ^-1, about ^{175.0 ± 25% × 10 -6 mL} -1, about ^{200.0 ± 25% × 10 -6 mL} -1, about ^{300.0 ± 25% × 10 -6 mL} -1, about ^{00.0 ± 25% × 10 -6 mL} -1, about ^{500.0 ± 25% × 10 -6 mL} -1, about ^{600.0 ± 25% × 10 -6 mL} -1 or about 700.0 ±, It may be 25% × 10 ⁻⁶ mL ⁻¹ or may exceed these values. For example, dnC ^* value is about 50 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 10 minutes of administration, about 125 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 15 minutes of administration, 20 minutes after administration About 150 ± 25% × 10 ⁻⁹ mL ⁻¹ or more, about 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 30 minutes of administration, about 450 ± 25% × 10 ⁻⁹ mL ⁻¹ after 45 minutes of administration Or more, about 600 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 1 hour of administration, about 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or more after 2 hours of administration, about 750 ± after 2.5 hours of administration 25% × 10 ^-9 mL ^-1 or more, 3 hours after administration, about 850 ± 25% × 10 ^-9 mL ^-1 or more, 3.3 hours after administration, about 900 ± 25% × 10 ^-9 mL ^-1 or more , about ^{950 ± 25% × 10 -9 mL} -1 or higher after 3.7 hours of dosing, at 4 administration After about ^{1000 ± 25% × 10 -9 mL} -1 or more, about ^{1050 ± 25% × 10 -9 mL} -1 or more after 4.33 hours of administration, about 1050 after 4.67 hours of administration ± 25% × 10 ^-9 mL ^-1 or more, 5 hours after administration: about 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 5.5 hours after administration: about 1000 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 6 of administration About 900 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after hour, about 700 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 8 hours of administration, about 650 ± 25% × 10 ⁻⁹ mL after 10 hours of administration ^-1 or less, about 500 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 12 hours of administration, about 400 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 14 hours of administration, about 350 ± after 16 hours of administration 25% × 10 ^-9 mL ^-1 or less, approximately 18 hours after administration 340 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, about 320 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 20 hours of administration, about 310 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 22 hours of administration Of about 300 ± 25% × 10 ⁻⁹ mL ⁻¹ or less after 24 hours of administration, about 180 ± 25% × 10 ⁻⁹ mL ⁻¹ or less of 36 hours after administration, about 140 ± 25% × after 48 hours of administration 10 ⁻⁹ mL ⁻¹ or less, or about 90 ± 25% × 10 ⁻⁹ mL ⁻¹ or less 72 hours after administration. In some embodiments, dnC ^* is 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 After time, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration Or 36 hours after administration. For example, the dnC ^* value is about 1.0 ± 25% × 10 ⁻⁹ mL ⁻¹ , about 1.0 ± 25% × 10 ⁻⁸ mL ⁻¹ , about 0.7 ± 25% × 10 ⁻⁷ mL ^{− 1} , about 1.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 2.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 3.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 4. 0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 1.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , or about 5.0 ± 25% It may be ^10-6 mL- ¹ or may be less than these values. In some embodiments, the dnC ^* value may be for a single dose. In some embodiments, dnC ^* values may relate to multiple dosing regimens (eg, once daily dosing). In some embodiments, the plasma concentrations used to calculate dnC ^* can be adjusted to reflect baseline plasma concentrations (eg, baseline plasma levels from a single daily dose) it can. C _max is defined as the peak plasma concentration of the compounds of the invention after administration. Or dnC ^* value is calculated at the time corresponding to C _max



If it can also be referred to as a dose normalized _{C max} or _{DNC max} ^*. In some embodiments, dnC _max ^* is greater than or equal to 1.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , 1.5 ± 25% × 10 ⁻⁶ mL ⁻¹ or greater, 2.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, 2.5 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, 3.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, 3.5 ± 25% × 10 ⁻⁶ mL ⁻¹ Or more, 4.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, 4.5 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, and 5.0 ± 25% × 10 ⁻⁶ mL ⁻¹ or more.

Transmucosal absorption also results in higher plasma concentrations of the compound as compared to oral administration. The plasma concentration may be an individual plasma concentration or an average plasma concentration when observing a plurality of individuals. The higher plasma concentration obtained by transmucosal absorption can be determined by measuring the plasma concentration of the administered compound, or by calculating the ratio of the product of plasma concentration ^* body mass to the administered dose. This is dose- and body mass-normalized plasma concentration (C) or dbmnC ^* , measured in kg · mL ⁻¹ . dbmnC ^* is calculated by determining the ratio of product plasma level x body mass to dose administered. For example, if 2.4 mg of cyclobenzaprine or amitriptyline is administered to a 70 kg animal, and the plasma level is 4.8 ng / mL at 15 minutes, the dbmnC ^{* at} 15 minutes is ((4.8 ng / mL) × (70 kg) / (2.4 mg)) = dbmnC _{(0.25 h)} ^* = 140.0 × 10 ⁻⁶ kg · mL ⁻¹ dbmnC ^* can be measured either at fixed or variable time points, for example at a time point corresponding to C _max . For example, dbmnC ^* is 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration After 3 hours, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration, 10 hours after administration, 11 hours after administration It can be measured after or 12 hours after administration. For example, the dbmn C ^* value is about 80.0 ± 25% × 10 ⁻⁷ kg · mL ⁻¹ , about 0.01 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 0.1 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 0.5 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 1.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 5.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 10.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 50.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 100.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 500.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , or about 1000.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , about 1250.0 ± ^{25% × 10 -6 kg · mL} -1, about ^{1500.0 ± 25% × 10 -6 kg} · mL -1, about 1750.0 ± 25% × ¹⁰ -6 kg mL ^-1, about ^{2000.0 ± 25% × 10 -6 kg} · mL -1, about ^{3000.0 ± 25% × 10 -6 kg} · mL -1, about 4000.0 ± 25% × ¹⁰ -6 kg • mL ⁻¹ , about 5000.0 ± 25% × 10 ⁻⁶ kg mL ⁻¹ , about 6000.0 ± 25% × 10 ⁻⁶ kg mL ⁻¹ , or about 7000.0 ± 25% × 10 ^{− It} may be ⁶ kg · mL ⁻¹ or may exceed these values. In some embodiments, dbmnC ^* is 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 After time, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration Or 36 hours after administration. For example, the value of dbmnC ^* is about 1.0 ± 25% × 10 ⁻⁹ mL ⁻¹ , about 1.0 ± 25% × 10 ⁻⁸ mL ⁻¹ , about 0.7 ± 25% × 10 ⁻⁷ mL ^{− 1} , about 1.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 2.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 3.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 4. 0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 5.0 ± 25% × 10 ⁻⁷ mL ⁻¹ , about 1.0 ± 25% × 10 ⁻⁶ mL ⁻¹ , or about 5.0 ± 25% It may be ^10-6 mL- ¹ or may be less than these values. In some embodiments, the dbmnC ^* values may relate to a single dose. In some embodiments, the dbmnC ^* values may relate to multiple dose regimens (eg, once daily dosing). In some embodiments, the plasma concentrations used to calculate dbmnC ^* may be adjusted to reflect baseline plasma concentrations (eg, baseline plasma levels from a single daily dose). it can. C _max is defined as the peak plasma concentration of the compounds of the invention after administration. Alternatively DbmnC ^* _value, as calculated at the time corresponding to the _{C max,} can also be referred to as a dose and body mass normalization _{C max} or _{dbmnC max} ^*. In some embodiments, dbmnC _max ^* is at least 10.0 ± 25% × 10 ⁻⁶ kg · mL ^{−1, at} least 15 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , at 20 ± 25% × 10 ^-6 kg · mL ^-1 or more, 25 ± 25% × 10 ^-6 kg · mL ^-1 or more, 30 ± 25% × 10 ^-6 kg · mL ^-1 or more, 35 ± 25% × ^10-6 kg · mL ^-1 or more, 40 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 45 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 50 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more . In some embodiments, dbmnC _max ^* is 100.0 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 150 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 200 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 250 ± 25% × 10 ⁻⁶ kg · kg · mL ⁻¹ or more, 300 ± 25% × 10 ⁻⁶ mL ⁻¹ or more, 350 ± 25% × 10 ⁻⁶ kg · mL ^-1 or more, 400 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 450 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more, 500 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or more .

As mentioned above, C _max is defined as the peak plasma concentration of the compounds of the invention after administration. By administering the composition of the invention for transmucosal absorption, it is possible to obtain higher _Cmax values than when the composition is administered orally. In some embodiments, the composition is at least 10 ng / mL, at least 11 ng / mL, at least 12 ng / mL, at least 13 ng / mL, at least 14 ng / mL, at least 15 ng / mL, at least 16 ng / mL, at least 17 ng / mL , 18 ng / mL or more, 19 ng / mL or more, 20 ng / mL or more, 21 ng / mL or more, 22 ng / mL or more, 23 ng / mL or more, 24 ng / mL or more, 25 ng / mL or more, 26 ng / mL or more, 27 ng / mL or more , 28 ng / mL or more, 29 ng / mL or more, 30 ng / mL or more, 31 ng / mL or more, 32 ng / mL or more, 33 ng / mL or more, 34 ng / mL or more, 35 ng / mL or more, 36 ng / mL or more, 37 ng / mL or more , 38 ng / mL or more, 39 ng / mL or more, 40 ng / mL or more, 50 ng / m At least 60 ng / mL, at least 70 ng / mL, at least 80 ng / mL, at least 90 ng / mL, at least 100 ng / mL, at least 120 ng / mL, at least 140 ng / mL, at least 160 ng / mL, at least 180 ng / mL, or at least 200 ng / mL Bring C _max for compounds above mL.

C _max can be measured after administration of either the initial dose or any dose of the composition of the invention. However, since the compositions and methods of the present invention can be used to extend the therapeutic regimen, plasma levels of the compounds useful in the compositions and methods do not return to zero between administrations (ie, There may be baseline levels of compounds in the blood circulation). Thus, the composition is not considered an absolute value compared to a starting plasma concentration of 0 ng / mL, and can provide a C _max that can be compared to the baseline level of the compound. In some embodiments, the composition comprises 10 ng / mL or more, 11 ng / mL or more, 12 ng / mL or more, 13 ng / mL or more of baseline levels (eg, plasma concentrations) of the compound measured immediately before the second administration. 14 ng / mL or more, 15 ng / mL or more, 16 ng / mL or more, 17 ng / mL or more, 18 ng / mL or more, 19 ng / mL or more, 20 ng / mL or more, 21 ng / mL or more, 22 ng / mL or more, 23 ng / mL or more Or more, 24 ng / mL or more, 25 ng / mL or more, 26 ng / mL or more, 27 ng / mL or more, 28 ng / mL or more, 29 ng / mL or more, 30 ng / mL or more, 31 ng / mL or more, 32 ng / mL or more, 33 ng / mL or more 34 ng / mL or more, 35 ng / mL or more, 36 ng / mL or more, 37 ng / mL or more 38 ng / mL or more, 39 ng / mL or more, 40 ng / mL or more, 50 ng / mL or more, 60 ng / mL or more, 70 ng / mL or more, 80 ng / mL or more, 90 ng / mL or more, 100 ng / mL or more, 120 ng / mL or more, Results in a compound _Cmax of greater than 140 ng / mL, greater than 160 ng / mL, greater than 180 ng / mL, or greater than 200 ng / mL. As used herein, "immediately before administration" means within 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute prior to administration.

As a result of the higher Cmax values achieved via sublingual administration, the area under the curve (AUC) of the plasma concentration of the compound also becomes greater over time as compared to the AUC obtained by oral administration. AUC is between two particular time (e.g., AUC 0-8H) or over between the outer挿期to infinity from 0 (AUC 0-∞h, AUC 0-∞ or AUC inf) can be measured. The AUC is typically described in units of ng · hr · mL −1 and thus, for example, in the experiment of FIG. 1 in a human subject administered a 5 mg immediate release cyclobenzaprine tablet, the AUC 0 −h h is , 103.1 ± 35.8 ng · hr · mL −1 , and AUC 0-168 h was 92.2 ± 29.9 ng · hr · mL −1 . As another example, administration of 2.4 mg of cyclobenzaprine sublingual tablet with basifying agent in a beagle experiment results in an AUC 0 of 135.6 ng · hr · mL −1 from 0 to 0.75 hours. -0.75 h was obtained. In the same experiment, AUC 0- 伴うh is 179.0 ± 50.2 ng · hr · mL −1 and AUC 0-10 h is 176.6 ± 49.9 ng for sublingual tablets with a basifying agent. It was hr · mL −1 . In a beagle experiment on a 2.4 mg sublingual tablet lacking the basifying agent, the AUC 0-0.75 h is 82.4 ng hr mL- 1 and the AUC 0-h h is 155.4 ± 64. 6 ng · hr · mL −1 , and AUC 0-10 h was 151.6 ± 64.0 ng · hr · mL −1 . An average dose of 1.79 mg i. v. In the beagle experiments (FIGS. 2 and 3) for cyclobenzaprine , AUC 0-∞h is 44.9 ± 4.15 ng · hr · mL −1 and AUC 0-24 h is 43.5 ± 3.77 ng · It was hr · mL −1 . In Beagle experiments (Figures 2 and 3) for sublingual solution cyclobenzaprine with an average dose of 1.79 mg, AUC 0-∞ h is 129.1 ± 36.4 ng · hr · mL -1 , AUC 0-24 h Was 126.9 ± 37.1 ng · hr · mL −1 . On the other hand, in the example according to the literature, when administering 2.5, 5.0 or 10 mg (10 mg in 70 kg of human corresponds to 0.14 mg / kg in beagle) of cyclobenzaprine immediate release tablet to human, respectively 11.1,23.0 and AUC 0-8H of 45.9ng · hr · mL -1 is obtained, AUC 0-∞, respectively 44.2,89.5 and 178.2ng · hr · mL -1 h were obtained (Winchell G. A. et al., "Cyclobenzaprine pharmacokinetics, including the effects of age, gender and hepatic insufficiency", J. Clin. Pharmacol 2002 42: 61). In some embodiments, for example, for a dose of 2.4 mg, AUC 0-20 min is about 0.04 ng · hr · mL −1 and AUC 0-30 min is about 0.13 ng · hr · mL −1 , AUC 0-45 min is about 0.33 ng · hr · mL −1 , AUC 0-1 h is about 0.61 ng · hr · mL −1 , AUC 0-2 h is about 2.10 ng · hr · mL is -1, AUC 0-2.5h is about 2.95ng · hr · mL -1, AUC 0-3h was about 3.93ng · hr · mL -1, AUC 0-3.3h is It is about 4.66 ng · hr · mL −1 , AUC 0-3.7 h is about 5.46 ng · hr · mL −1 , and AUC 0−4 h is about 6.27 ng · hr · mL −1 , AUC 0-4.3h is about 7.12 a g · hr · mL -1, AUC 0-4.7h is about 7.99ng · hr · mL -1, AUC 0-0-5h is about 8.81ng · hr · mL -1, AUC 0-5.5 h is about 10.06 ng · hr · mL −1 , AUC 0-6 h is about 11.27 ng · hr · mL −1 , AUC 0-8 h is about 15.11 ng · hr · It is mL −1 , AUC 0-12 h is about 50.30 ng · hr · mL −1 , and AUC 0 -Inf is about 60.97 ng · hr · mL −1 . In some embodiments (using TNX-102 SL 2.8), AUC 0-20 min is about 0.04 ng · hr · mL −1 and AUC 0-30 min is about 0.15 ng · hr · mL − 1 , AUC 0-45 min is about 0.39 ng · hr · mL −1 , AUC 0-1 h is about 0.72 ng · hr · mL −1 , AUC 0-2 h is about 2.45 ng ·· a hr · mL -1, AUC 0-2.5h is about 3.45ng · hr · mL -1, AUC 0-3h was about 4.59ng · hr · mL -1, AUC 0-3 .3 h is approximately 5.44 ng · hr · mL −1 , AUC 0-3.7 h is approximately 6.37 ng · hr · mL −1 , and AUC 0-4 h is approximately 7.32 ng · hr · mL − is 1, AUC 0-4.3h is A 8.30ng · hr · mL -1, AUC 0-4.7h is about 9.32ng · hr · mL -1, AUC 0-0-5h is about 10.27ng · hr · mL -1 AUC 0-5.5 h is about 11.74 ng · hr · mL −1 , AUC 0-6 h is about 13.14 ng · hr · mL −1 , AUC 0-8 h is about 17.63 ng ·· It is hr · mL −1 , AUC 0-12 h is about 58.68 ng · hr · mL −1 , and AUC 0 -Inf is about 71.13 ng · hr · mL −1 . AUC can also be compared to the dose administered to produce a ratio of AUC to dose, sometimes referred to as dose normalized AUC or dnAUC. The dose normalized dnAUC 0-∞h for the human data in FIG. 1 above is 20.6 × 10 −6 hr mL −1 . The dose normalized AUC 0-0.75 h (dnAUC 0-0.75 h ) for the aforementioned beagle data is: dnAUC 0-0.75 h = 135.6 6 ng · hr · mL -1 /2.4 mg = 56.5 × 10 −6 hr · mL −1 . In the beagle experiments (Figures 2 and 3) for an average dose of 1.79 mg of IV cyclobenzaprine, dnAUC 0-∞h is 25.04 x 10 -6 hr mL -1 and dnAUC 0-24h is 24. It was 2 * 10 < -6 > hr * mL < -1 >. In beagle experiments (Figures 2 and 3) with a sublingual cyclobenzaprine solution with an average dose of 1.79 mg, dnAUC 0-∞h is 71.95 × 10 -6 hr mL -1 and dnAUC 0-24h is It was 70.72 * 10 < -6 > hr * mL < -1 >. The dose normalized AUC 0-8h (dnAUC 0-8h ) for the above-mentioned human data (by Winchell et al.) Is 4.4 × 10 − for 2.5, 5.0 and 10 mg of cyclobenzaprine dose, respectively. 6 hr · mL -1, is 4.6 × 10 -6 hr · mL -1 and 4.6 × 10 -6 hr · mL -1 . The dose normalized dnAUC 0-∞h for the above-mentioned human data (by Winchell et al.) Is 17.7 × 10 −6 hr · mL − for cyclobenzaprine doses of 2.5, 5.0 and 10 mg respectively 1, is a 17.9 × 10 -6 hr · mL -1 and 17.8 × 10 -6 hr · mL -1 . In some embodiments, dnAUC 0-20 min is about 0.02 ± 25% × 10 −6 hr · mL −1 and dnAUC 0-30 min is about 0.05 ± 25% × 10 −6 hr · mL -1 , and dnAUC 0-45 min is about 0.15 ± 25% × 10 −6 hr · mL −1 , and dnAUC 0-1 h is about 0.25 ± 25% × 10 −6 hr · mL −1 DnAUC 0-2 h is about 0.90 ± 25% × 10 −6 hr · mL −1 , and dnAUC 0-2.5 h is about 1.2 ± 25% × 10 −6 hr · mL −1 DnAUC 0-3 h is about 1.6 ± 25% × 10 −6 hr · mL −1 , and dnAUC 3.3 h is about 1.8 ± 25% × 10 −6 hr · mL −1 , dnAUC 0-3.7h about 2.3 ± 25% × 10 -6 hr mL is -1, dnAUC 0-4h is about 2.6 ± 25% × 10 -6 hr · mL -1, dnAUC 0-4.3h about 3.0 ± 25% × 10 -6 hr · mL −1 , and dnAUC 0-4.7 h is about 3.3 ± 25% × 10 −6 hr · mL −1 , and dnAUC 0-5 h is about 3.7 ± 25% × 10 −6 hr · mL −1 , and dnAUC 0−5.5 h is about 4.2 ± 25% × 10 −6 hr · mL −1 , and dnAUC 0-6 h is about 4.7 ± 25% × 10 −6 hr · a mL -1, dnAUC 0-8h is 6.3 ± 25% × 10 -6 hr · mL -1, dnAUC 0-12h may be about 20 ± 25% × 10 -6 hr · mL -1 , DnAUC 0-∞ h is about 25 ± 25% × 10 −6 hr · mL −1 . In some embodiments, dnAUC 0-8h is 5 ± 25% × 10 −6 hr · mL −1 or higher, 6 ± 25% × 10 −6 hr · mL −1 or higher, 7 ± 25% × 10 − 6 hr · mL −1 or more, 8 ± 25% × 10 −6 hr · mL −1 or more, 9 ± 25% × 10 −6 hr · mL −1 or more, 10 ± 25% × 10 −6 hr · mL − 1 or more, 11 ± 25% × 10 −6 hr · mL −1 or more, 12 ± 25% × 10 −6 hr · mL −1 or more, 13 ± 25% × 10 −6 hr · mL −1 or more, 14 ± 25% × 10 −6 hr · mL −1 or more, 15 ± 25% × 10 −6 hr · mL −1 or more, 16 ± 25% × 10 −6 hr · mL −1 or more, 17 ± 25% × 10
6 −6 hr · mL −1 or more, 18 ± 25% × 10 −6 hr · mL −1 or more, or 19 ± 25% × 10 −6 hr · mL 1 or more. In some embodiments, dnAUC 0-8h is at least 20 ± 25% × 10 −6 hr mL −1, at least 22 ± 25% × 10 6 hr mL −1 , at 24 ± 25% × 10 − 6 hr · mL −1 or more, 26 ± 25% × 10 −6 hr · mL −1 or more, 28 ± 25% × 10 −6 hr · mL −1 or more, or 30 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-8h is at least 40 ± 25% × 10 −6 hr · mL −1, at least 50 ± 25% × 10 −6 hr · mL −1 , at 60 ± 25% × 10 − 6 hr · mL −1 or more, 70 ± 25% × 10 −6 hr · mL −1 or more, 80 ± 25% × 10 −6 hr · mL −1 or more, or 90 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-8h is at least 100 ± 25% × 10 −6 hr mL −1, at least 120 ± 25% × 10 −6 hr mL −1 , at 140 ± 25% × 10 − 6 hr · mL −1 or more, 160 ± 25% × 10 −6 hr · mL −1 or more, 180 ± 25% × 10 −6 hr · mL −1 or more, or 200 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-10 h is at least 5 ± 25% × 10 −6 hr mL −1, at least 6 ± 25% × 10 6 hr mL −1 , at 7 ± 25% × 10 − 6 hr · mL −1 or more, 8 ± 25% × 10 −6 hr · mL −1 or more, 9 ± 25% × 10 −6 hr · mL −1 or more, 10 ± 25% × 10 −6 hr · mL − 1 or more, 11 ± 25% × 10 −6 hr · mL −1 or more, 12 ± 25% × 10 −6 hr · mL −1 or more, 13 ± 25% × 10 −6 hr · mL −1 or more, 14 ± 25% × 10 −6 hr · mL −1 or more, 15 ± 25% × 10 −6 hr · mL −1 or more, 16 ± 25% × 10 −6 hr · mL −1 or more, 17 ± 25% × 10 − 6 hr · mL -1 or more, 18 ± 25% × 10 -6 hr · mL -1 or more, or 19 ± 25% × 10 -6 h · ML -1 or more. In some embodiments, dnAUC 0-10 h is at least 20 ± 25% × 10 −6 hr mL −1, at least 22 ± 25% × 10 6 hr mL −1 , at 24 ± 25% × 10 − 6 hr · mL −1 or more, 26 ± 25% × 10 −6 hr · mL −1 or more, 28 ± 25% × 10 −6 hr · mL −1 or more, or 30 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-10 h is 40 ± 25% × 10 −6 hr mL −1 or higher, 50 ± 25% 10 6 hr mL −1 or higher, 60 ± 25% × 10 − 6 hr · mL −1 or more, 70 ± 25% × 10 −6 hr · mL −1 or more, 80 ± 25% × 10 −6 hr · mL −1 or more, or 90 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-10h is at least 100 ± 25% × 10 −6 hr · mL −1, at least 120 ± 25% × 10 −6 hr · mL −1 , at 140 ± 25% × 10 − 6 hr · mL −1 or more, 160 ± 25% × 10 −6 hr · mL −1 or more, 180 ± 25% × 10 −6 hr · mL −1 or more, or 200 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-12h is 20 ± 25% × 10 −6 hr mL −1 or higher, 30 ± 25% 10 6 hr mL −1 or higher, 40 ± 25% × 10 − 6 hr · mL −1 or higher, 50 ± 25% × 10 −6 hr · mL −1 or higher, 60 ± 25% × 10 −6 hr · mL −1 or higher, or 70 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-12h is 80 ± 25% × 10 −6 hr mL −1 or higher, 90 ± 25% 10 6 hr mL −1 or higher, 100 ± 25% × 10 − 6 hr · mL −1 or more, 120 ± 25% × 10 −6 hr · mL −1 or more, 160 ± 25% × 10 −6 hr · mL −1 or more, or 180 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-24h is 24 ± 25% × 10 −6 hr · mL −1 or higher, or 25 ± 25% × 10 −6 hr · mL −1 or higher, 30 ± 25% × 10 −6 hr · mL −1 or more, 35 ± 25% × 10 −6 hr · mL −1 or more, 40 ± 25% × 10 −6 hr · mL −1 or more, 50 ± 25% × 10 −6 hr · mL -1 or more, 60 ± 25% × 10 −6 hr · mL −1 or more, 70 ± 25% × 10 −6 hr · mL −1 or more, 80 ± 25% × 10 −6 hr · mL −1 or more, or 90 ± 25% × 10 −6 hr · mL −1 or more. In some embodiments, dnAUC 0-24h is at least 100 ± 25% × 10 −6 hr · mL −1, at least 110 ± 25% × 10 −6 hr · mL −1 , at 120 ± 25% × 10 − 6 hr · mL −1 or more, 130 ± 25% × 10 −6 hr · mL −1 or more, 140 ± 25% × 10 −6 hr · mL −1 or more, or 150 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-24h is at least 160 ± 25% × 10 −6 hr mL −1, at least 170 ± 25% × 10 6 hr mL −1 , at 180 ± 25% × 10 − 6 hr · mL −1 or more, 190 ± 25% × 10 −6 hr · mL −1 or more, 200 ± 25% × 10 −6 hr · mL −1 or more, or 210 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-24h is greater than or equal to 220 ± 25% × 10 −6 hr · mL −1 , 240 ± 25% × 10 −6 hr · mL −1 or greater, 250 ± 25% × 10 − 6 hr · mL −1 or more, 260 ± 25% × 10 −6 hr · mL −1 or more, 270 ± 25% × 10 −6 hr · mL −1 or more, or 280 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-∞h is 24 ± 25% × 10 −6 hr · mL −1 or higher, or 25 ± 25% × 10 −6 hr · mL −1 or higher, 30 ± 25% × 10 −6 hr · mL −1 or more, 35 ± 25% × 10 −6 hr · mL −1 or more, 40 ± 25% × 10 −6 hr · mL −1 or more, 50 ± 25% × 10 −6 hr · mL -1 or more, 60 ± 25% × 10 −6 hr · mL −1 or more, 70 ± 25% × 10 −6 hr · mL −1 or more, 80 ± 25% × 10 −6 hr · mL −1 or more, Or 90 ± 25% × 10 −6 hr · mL −1 or more. In some embodiments, dnAUC 0-∞h is at least 100 ± 25% × 10 −6 hr · mL −1, at least 110 ± 25% × 10 −6 hr · mL −1 , at 120 ± 25% × 10 −6 hr · mL −1 or more, 130 ± 25% × 10 −6 hr · mL −1 or more, 140 ± 25% × 10 −6 hr · mL −1 or more, or 150 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-∞h is at least 160 ± 25% × 10 −6 hr · mL −1, at least 170 ± 25% × 10 −6 hr · mL −1 , at 180 ± 25% × 10 −6 hr · mL −1 or more, 190 ± 25% × 10 −6 hr · mL −1 or more, 200 ± 25% × 10 −6 hr · mL −1 or more, or 210 ± 25% × 10 −6 hr · mL -1 or more. In some embodiments, dnAUC 0-∞h is greater than or equal to 220 ± 25% × 10 −6 hr · mL −1 , 240 ± 25% × 10 −6 hr · mL −1 or greater, 250 ± 25% × 10 −6 hr · mL −1 or more, 260 ± 25% × 10 −6 hr · mL −1 or more, 270 ± 25% × 10 −6 hr · mL −1 or more, or 280 ± 25% × 10 −6 hr · mL -1 or more.

Also, the product of AUC and body mass can be compared to the dose administered to produce a product of AUC × body mass to dose, which is herein referred to as dose- and body mass-normalized AUC or dbmnAUC. It is called. The dose- and body mass-normalized dbmnAUC _{0-∞h for} the human data of FIG. 1 above is approximately 140.6 × 10 ⁻⁶ kg · hr · mL ⁻¹ for a 70 kg human. The _dose- and body mass-normalized AUC _{0-0.75 h} (dbmnAUC _{0-0.75 h} ) (the average body mass of the beagle was 12.5 kg) for the aforementioned beagle data, dbmnAUC _{0-0.75 h} = 12. 5 kg × 135.6 ng · hr · mL ⁻¹ /2.4 mg = 708 × 10 ⁻⁶ kg · hr · mL ⁻¹ . In the beagle experiments (Figures 2 and 3) for an average dose of 1.79 mg of IV cyclobenzaprine, the dbmnAUC _0-∞h is 12.5 kg x 25.04 x 10 ^-6 hr mL ^-1 , dbmnAUC _{0- 24 h} was 314 × 10 ⁻⁶ kg · hr · mL ⁻¹ . In beagle experiments (Figures 2 and 3) with a sublingual cyclobenzaprine solution with an average dose of 1.79 mg, the dbmnAUC _0-∞h is 12.5 kg x 71.95 x 10 ^-6 hr mL ^-1 , the dbmnAUC _{0-24 h} was 886 × 10 ⁻⁶ kg · hr · mL ⁻¹ . The dbmnAUC _0-8h for the aforementioned human data (according to Winchell et al.) Assuming a 70 kg human is approximately 70 kg × 4.4 ± 25% for _2.5 , 5.0 and 10 mg cyclobenzaprine doses respectively × 10 ⁻⁶ hr · mL ⁻¹ = 308 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 322 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ and 322 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ . The dose normalized dbmnAUC _0-∞h for the above human data (by Winchell et al.) Is 70 kg × 17.7 ± 25% × 10 ^{− for} 2.5, 5.0 and 10 mg cyclobenzaprine doses, respectively. ⁶ hr · mL ⁻¹ = 1239 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 1253 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and 1246 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ In some embodiments, dbmnAUC 0-20 _min is about 1.1 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ and dbmnAUC _{0-30 min} is about 3.7 ± 25% × 10 ⁻⁶ kg・ Hr · mL ⁻¹ , and dbmnAUC 0-45 _min is about 9.7 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _{0-1 h} is about 18 ± 25% × 10 ⁻⁶ kg · Hr · mL ^-1 , dbmnAUC _0-2h is about 62 ± 25% × 10 ^-6 kg · hr · mL ^-1 , dbmnAUC _{0-2.5 h} is approximately 86 ± 25% × 10 ^-6 kg · Hr · mL ^-1 , dbmnAUC _0-3h is about 115 ± 25% × 10 ^-6 kg · hr · mL- ¹ , dbmnAUC _{3.3 h} is about 135 ± 25% × 10 ^-6 kg · hr・ ML ^-1 DbmnAUC 0-3.7 _h is about 160 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _{0-4 h} is about 180 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ DbmnAUC 0-4.3 _h is approximately 210 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _{0-4.7 h} is approximately 230 ± 25% × 10 ⁻⁶ kg · hr · mL ^-1 , and dbmnAUC 0-5 _h is approximately 260 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _{0-5.5 h} is approximately 290 ± 25% × 10 ⁻⁶ kg · hr · mL ^-1 , and dbmnAUC _0-6h is approximately 330 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _0-8h is 440 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ Yes, dbmnA UC _{0-12 h} is about 1500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , and dbmnAUC _0−Inf is about 1800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ . In some embodiments, dbmnAUC _0-8h is at least 350 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ . In some embodiments, dbmnAUC _0-8h is greater than or _equal to 400 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ , 500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or greater, 600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 700 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 900 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-8h is 1000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1200 ± 25% × 10 ⁻⁶ kg · hr · mL ¹ or more, 1400 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2000 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-10h is 400 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 600 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 700 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 900 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-10h is greater than or _equal to 1000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 1200 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1400 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2000 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-12h is at least 500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 700 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 800 ± 25% × 10 ⁻⁶ kg · hr · mL ¹ or more, or 900 ± 25% × 10 ⁻⁶ kg · hr · mL ¹ or more . In some embodiments, dbmnAUC _0-12h is 1000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1200 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1400 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2000 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-24h is at least 500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 700 ± 25 % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 800 ± 25% × 10 ⁻⁶ kg · hr · mL ¹ or more, or 900 ± 25% × 10 ⁻⁶ kg · hr · mL ¹ or more . In some embodiments, dbmnAUC _0-24h is greater than or _equal to 1000 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , 1100 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ or more, 1200 ± 25% × 10 ^{− 6} kg · hr · mL ⁻¹ or more, 1300 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1400 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 1500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-24h is greater than or _equal to 1600 ± 25% × 10 ⁻⁶ kg · hr · mL ^−1, or more than 1700 ± 25% × 10 ⁻⁶ kg · hr · mL ^−1, or 1800 ± 25. % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1900 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2100 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-24h is greater than or _equal to 2200 ± 25% × 10 ⁻⁶ kg · hr · mL ^−1, greater than or _{equal to} 2400 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 2500 ± 25. % × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2700 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2800 It is ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dnAUC _0-∞h is greater than or _equal to 240 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , or 250 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 300 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 35 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 400 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 700 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more , 800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 900 ± 25% × 10 ⁻⁶




kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-∞h is greater than or _equal to 1000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 1100 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1200 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1300 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1400 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or It is 1500 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-∞h is greater than or _equal to 1600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 1700 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 1900 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or 2100 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-∞h is greater than or _equal to 2200 ± 25% × 10 ⁻⁶ kg · hr · mL ^−1, greater than or _{equal to} 2400 ± 25% × 10 ⁻⁶ kg · hr · mL ^−1, or 250 ±. 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2600 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 2700 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ or more, or 2800 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-∞h is greater than or _equal to 5000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 10000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 15000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 20000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 25000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, or It is 30000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more. In some embodiments, dbmnAUC _0-∞h is greater than or _equal to 35000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ , 40000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 45000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 50000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more, 55000 ± 25% × 10 ⁻⁶ hr · mL ⁻¹ or more, or 60000 ± 25% × 10 ⁻⁶ kg · hr · mL ⁻¹ or more.

In some embodiments, the composition of the present invention is a composition that provides a bioequivalence effect to the compositions described herein. Bioequivalence can be determined by AUC, _Cmax , _tmax , mean absorption time, metabolite plasma concentration, mean residence time, rate constant, rate profile, and _Cmax normalized to AUC. An exemplary test of bioequivalence is the confidence interval of C _max and / or AUC, which is approximately 80%, 85%, 90%, 91%, 92%, 93% of the given compound. 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110% , 115%, 120%, or 125%.

In some embodiments, the methods of the present invention are methods of providing bioequivalence effects to the compositions described herein. Bioequivalence can be determined by AUC, _Cmax , _tmax , mean absorption time, metabolite plasma concentration, mean residence time, rate constant, rate profile, and _Cmax normalized to AUC. An exemplary test of bioequivalence is the confidence interval of C _max and / or AUC, which is approximately 80%, 85%, 90%, 91%, 92%, 93% of the given compound. 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110% , 115%, 120%, or 125%.

In some embodiments, the methods and compositions of the present invention cause the administered compounds comprising biologically active metabolites of the compounds to be cleared from plasma more rapidly than when administered orally. This is beneficial as the clearance of the compound can help to reduce side effects. For example, if the subject ingests a sublingual composition comprising cyclobenzaprine or amitriptyline prior to sleep, cyclobenzaprine or amitriptyline is rapidly absorbed but substantially metabolized by the time the subject wakes up. Because it is excreted, it can minimize fatigue, somnolence and lingering sensations when waking up. In some embodiments, the plasma level of the compound is 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, or at least 50% of C _{max by} 15 hours after administration. In some embodiments, the plasma levels of the _compound, at least _50% of _{C max} to 4 hours after the _{t max,} at least _55% of _{C max} to 4 hours after the _{t max,} until after 4 hours of _{t max} at least _60% of _{C max,} at least _65% of _{C max} to 4 hours after the _{t max,} at least _70% of _{C max} to 4 hours after the _{t max,} at least the _{C max} by 4 hours _{post-t max 75%,} at least _80% of _{C max} to 4 hours after the _{t max,} at least _85% of _{C max} to 4 hours after the _{t max,} at least _90% of _{C max} to 4 hours after the _{t max, t max} at least _{91%, t} least _92% of _{C max} to 4 hours after the _{max, t C max} to 4 hours after the _max of _{C max} to 4 hours after the At least _93%, at least _94% of _{C max} to 4 hours after the _{t max,} at least _95% of _{C max} to 4 hours after the _{t max,} at least 96% of _{C max} to 4 hours after the _{t max,} t At least _97% of _{C max} to 4 hours after the _max, at least 98% of _{C max} to 4 hours after the _{t max,} or _t least 99% of the _{C max} in until after 4 hours _max decreases. In some embodiments, the plasma levels of the compound, at least 50% of the _{C max} by 8 hours after administration, at least 55% of _{C max} by 8 hours after administration, _{C max} by 8 hours after administration Of at least 60% of _Cmax by 8 hours after administration, at least 70% of _Cmax by 8 hours of administration, at least 75% of _{Cmax by} 8 hours of administration, 8 of administration at least 80% of the _{C max} by time after, at least 85% of _{C max} by 8 hours after administration, at least 90% of _{C max} by 8 hours after administration, at least the _{C max} by 8 hours after administration 91%, at least 92% of _{C max} by 8 hours after administration, at least 93% of _{C max} by 8 hours after administration, less of _{C max} by 8 hours after administration Both 94%, at least 95% of _{C max} by 8 hours after administration, at least 96% of _{C max} by 8 hours after administration, at least 97% of _{C max} by 8 hours after administration, 8 hours of administration There is a reduction of at least 98% of C _max by late, or at least 99% of C _{max by} 8 hours after administration. In some embodiments, the plasma levels of the compound, at least 50% of _{C max} to 4 hours after the administration, at least 55% of _{C max} to 4 hours after the administration, _{C max} to 4 hours after administration At least 60% of _Cmax by 4 hours after administration, at least 70% of _Cmax by 4 hours after administration, at least 75% of _{Cmax by} 4 hours after administration, 4 at least 80% of the _{C max} by time after, at least 85% of _{C max} to 4 hours after the administration, at least 90% of _{C max} to 4 hours after administration, at least the _{C max} to 4 hours after administration 91%, at least 92% of _{C max} to 4 hours after the administration, at least 93% of _{C max} to 4 hours after administration, less of _{C max} to 4 hours after administration Both 94%, at least 95% of _{C max} to 4 hours after the administration, at least 96% of _{C max} to 4 hours after the administration, at least 97% of _{C max} to 4 hours after administration, four hours of administration There is a decrease of at least 98% of C _max by late, or at least 99% of C _{max by} 4 hours after administration.

In some embodiments, the compositions or methods of the present invention provide high C _max and low t _{max of} cyclobenzaprine or amitriptyline in combination with high clearance. For example, a composition or method of the invention administered at least once a day for four or more days provides a C _max of about 20 to about 200 ng / mL after about 0.05 to about 2.5 hours of administration. At the same time, a minimum plasma concentration of about 1 to about 5 ng / mL can be obtained after about 22 to about 26 hours of administration. In some embodiments, the composition is administered within 2 hours before sleep. In some embodiments, the method is a method for reducing fibromyalgia symptoms in a human patient.

In some embodiments, the methods and compositions of the present invention cause the compounds to be cleared from plasma more rapidly than when administered orally. This is beneficial as the clearance of the compounds can help reduce the accumulation of cyclobenzaprine or amitryptiline in the body when administered on a long-term dosing schedule by nightly dosing. The minimum concentration or C _min can be determined by measuring the plasma concentration of the administered compound, which is either a constant time point or a variable time point, eg a time point after the time point corresponding to C _max , eg C It can be measured after 23 hours of _max . C _min can be measured after a single dose, or after chronic administration of continuous, multiple, or, for example, once daily doses. For example, C _min is 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 8 hours after administration, 9 hours after administration It can be measured after 10 hours, 11 hours after administration, or 12 hours after administration. In some embodiments, C _min is 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration, 16 After time, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration Or 36 hours after administration. In some embodiments, the composition is 10 pg / mL or less, 11 pg / mL or less, 12 pg / mL or less, 13 pg / mL or less, 14 pg / mL or less, 15 pg / mL or less, 16 pg / mL or less, 17 pg / mL or less 18 pg / mL or less, 19 pg / mL or less, 20 pg / mL or less, 21 pg / mL or less, 22 pg / mL or less, 23 pg / mL or less, 24 pg / mL or less, 25 pg / mL or less, 26 pg / mL or less, 27 pg / mL or less 28 pg / mL or less, 29 pg / mL or less, 30 pg / mL or less, 31 pg / mL or less, 32 pg / mL or less, 33 pg / mL or less, 34 pg / mL or less, 35 pg / mL or less, 36 pg / mL or less, 37 pg / mL or less , 38 pg / mL or less, 39 pg / mL or less, 40 pg / mL or less, 50 pg / m Or less, 60 pg / mL or less, 70 pg / mL or less, 80 pg / mL or less, 90 pg / mL or less, 100 pg / mL or less, 120 pg / mL or less, 140 pg / mL or less, 160 pg / mL or less, 180 pg / mL or less, or 200 pg / mL or Bring C _min for compounds below mL. In some embodiments, the composition is less than 100 pg / mL, less than 110 pg / mL, less than 120 pg / mL, less than 130 pg / mL, less than 140 pg / mL, less than 150 pg / mL, less than 160 pg / mL, less than 170 pg / mL 180 pg / mL or less, 190 pg / mL or less, 200 pg / mL or less, 210 pg / mL or less, 220 pg / mL or less, 230 pg / mL or less, 240 pg / mL or less, 250 pg / mL or less, 260 pg / mL or less, 270 pg / mL or less 280 pg / mL or less, 290 pg / mL or less, 300 pg / mL or less, 310 pg / mL or less, 320 pg / mL or less, 330 pg / mL or less, 340 pg / mL or less, 350 pg / mL or less, 360 pg / mL or less, 370 pg / mL or less , 380pg / mL Below, 390 pg / mL or less, 400 pg / mL or less, 500 pg / mL or less, 600 pg / mL or less, 700 pg / mL or less, 800 pg / mL or less, 900 pg / mL or less, 1.0 ng / mL or less, 1.20 ng / mL or less , 1.40ng / mL or less, 1.60ng / mL or less, results in a _{C min} of 1.80ng / mL or less, or 2.00ng / mL following compounds. In some embodiments, the composition is 3.0 ng / mL or less, 4.0 ng / mL or less, 5.0 ng / mL or less, 6.0 ng / mL or less, 7.0 ng / mL or less, 8.0 ng / mL Bring C _min for compounds below mL, or below 10.0 ng / mL. The minimum concentration at 24 hours or C _{min (24)} can be determined by measuring the plasma concentration of the administered compound approximately 24 hours after the last dose or just prior to the next dose. C _{min (24)} becomes significant as a plasma value or by calculating the ratio of C _{min (24)} to the dose administered, which is the dose normalized minimum plasma concentration or dn C _{min (24)} ^* . dnC _{min (24)} ^* is calculated by determining the ratio of plasma levels to the dose administered. For example, in studies with PO administration of 5.0 mg of cyclobenzaprine immediate release tablets (shown in FIG. 1), the average C _{min (24)} is 1.384 ng / mL at 24 hours, dn C _{min (24)} ^* ((1.384 ng / mL) / (5.0 mg)) = 0.2680 ng / (mg · mL) or 0.27680 × 10 ⁻⁶ ml ⁻¹ . In another example, in studies in which 2.4 mg of cyclobenzaprine sublingual tablet were administered, the mean C _{min (24)} is 706.55 ng / mL at 24 hours, and dn C _{min (24)} ^* 706.55 ng / mL) / (2.4 mg)) = 294.40 ng / (mg · mL) or 0.29440 × 10 ⁻⁶ mL ⁻¹ . In some embodiments, dnC _{min (24)} ^* is less than or equal to 1.0 ± 25% × 10 ⁻⁶ mL ^−1, less than or equal to 0.9 ± 25% × 10 ⁻⁶ mL ⁻¹ , 0.8 ± 25 % × 10 ⁻⁶ mL ⁻¹ or less, 0.7 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 0.6 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 0.5 ± 25% × 10 ⁻⁶ It is less than or equal to mL ⁻¹ , 0.4 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, or 0.3 ± 25% × 10 ⁻⁶ mL ⁻¹ or less. In some embodiments, dnC _{min (24)} ^* is less than or equal to 240 ± 25% × 10 ⁻⁹ mL ^−1, less than or equal to 220 ± 25% × 10 ⁻⁹ mL ⁻¹ , 200 ± 25% × 10 ⁻⁹ mL ^-1 or less, 180 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 160 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 140 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 120 ± 25% × 10 ^{− 6} mL ⁻¹ or less, 100 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 80 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 60 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 40 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 20 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, or 10 ± 25% × 10 ⁻⁹ mL ⁻¹ or less. In some embodiments, dnC _{min (24)} ^* is less than 9 ± 25% × 10 ⁻⁹ mL ^−1, less than 9 ± 25% × 10 ⁻⁶ mL ⁻¹ , 7 ± 25% × 10 ⁻⁹ mL ^-1 or less, 6 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 5 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 4 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 3 ± 25% × 10 ^{− 9} mL ⁻¹ or less, 2 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, or 1 ± 25% × 10 ⁻⁹ mL ⁻¹ or less.

Dose - and body mass - normalized _{C min} or _{dbmnC min} ^* is calculated by determining the ratio of the dose administered and the product of the plasma levels and body mass. DbmnC _min ^* or dbmnC _{min (24)} ^* at 24 hours: approximately 24 hours after or immediately following the last dose of the plasma concentration of the compound administered on a once-a-day dosing schedule, such as a dosing schedule at bedtime It can be determined by measuring just prior to administration. dbmnC _min ^* can be determined by measuring the plasma concentration of the administered compound, which is determined at a fixed time point, for example at 24 hours after administration (C _{min (24)} ^* ) or at a variable time point for example point after time corresponding to the _{C max,} it may be measured, for example, to 23 hours after _{C max.} For example, in studies in which 5.0 mg of cyclobenzaprine immediate release tablet were administered PO (shown in FIG. 1), the average C _{min (24)} ^* is 1.384 ng / mL at 24 hours, assuming 70 kg of human Then, the approximate dbmnC _{min (24)} ^* was 70 kg × ((1.384 ng / mL) / (5.0 mg)) = 19.4 × 10 ⁻⁶ kg · mL ⁻¹ . For example, in studies that received 2.4 mg of cyclobenzaprine sublingual tablets, the average C _{min (24)} is 706.55 ng / mL at 24 hours, and dnC _{min (24)} ^* is ((706.55 ng /ML)/(2.4 mg)) = 294.40 ng / (mg · mL) or 294.40 × 10 ⁻⁹ mL ⁻¹ , assuming a 70 kg human, the approximate dbmnC _{min (24)} ^* is It was 70 kg x ((706.55 ng / mL) / (2.4 mg)) = 20.608 ^10-6 kgmL- ¹ . In some embodiments, dbmnC _{min (24)} ^* is less than or equal to 1.0 ± 25% × 10 ⁻⁶ kg · mL ^−1, less than or equal to 0.9 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , 0 Less than or equal to 8 ± 25% × 10 ⁻⁶ kg · mL ^−1, less than or equal to 0.7 ± 25% × 10 ⁻⁶ kg · mL ^−1, or less than 0.6 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ 0.5 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 0.4 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, or 0.3 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ It is below. In some embodiments, dbmnC _{min (24)} ^* is less than or equal to 240 ± 25% × 10 ⁻⁹ mL ^−1, less than or equal to 220 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ , 200 ± 25% × 10 ^{− 9} kg · mL ⁻¹ or less, 180 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 160 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, 140 ± 25% × 10 ⁻⁹ kg · mL ^{− 1} or less, 120 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 100 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 80 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 60 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 40 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 20 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, or 10 ± 25% × 10 ^{It is -9} kg * mL- ¹ or less. In some embodiments, dbmnC _{min (24)} ^* is less than ⁹ ± 25% × 10 ⁻⁹ kg · mL ⁻¹ , 9 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 7 ± 25% × 10 ^{− 9} kg · mL ⁻¹ or less, 6 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 5 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, 4 ± 25% × 10 ⁻⁹ kg · mL ^{− 1} or less, 3 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 2 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, or 1 ± 25% × 10 ⁻⁹ kg · mL ¹ or less .

In some embodiments, the methods and compositions of the present invention allow the compounds to be absorbed into plasma without intestinal or hepatic metabolism, thereby reducing the degree of demethylation by p450. This is beneficial because the demethylation by p450 converts cyclobenzaprine to a long half-life norcyclobenzaprine and amitriptyline to a long half-life nortriptyline. Lower concentrations of the secondary amine metabolites norcyclobenzaprine and nortriptyline result in the tertiary amines cyclobenzaprine and nortriptyline being more rapidly cleared from the plasma and the body, and clearance of the compound It is beneficial because nightly administration can help reduce the accumulation of compounds (drugs and metabolites) that act on the body when administered on a chronic dosing schedule. The ratio of plasma concentration of the metabolite to the dose of drug administered is the dose normalized concentration of the metabolite or dnC _met ^* . The ratio of plasma concentration of norcyclobenzaprine to dose of cyclobenzaprine administered is the dose normalized concentration of norcyclobenzaprine or dnC _met (norcyclo) ^* . The ratio of the plasma concentration of nortriptyline to the dose of amitriptyline administered is the dose normalized concentration of nortriptyline or dnC _met (nortrip) ^* . dnC _met ^* can be measured at various times after administration of the compound, either after a single dose or after multiple doses. The dnC _met ^* can be measured either at constant or variable time points, for example at a time point corresponding to C _max . For example, dnC _met ^* is 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration Can. In some embodiments, dnC _met ^* is administered 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration 16 hours, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration It can be measured after or 36 hours after administration. DnC _met ^* or dnC _{met (24)} ^{* at} 24 hours may be given once daily, for example, at about 24 hours after the last dose or after the plasma concentration of the compound administered on the bedtime dosing schedule It can be determined by measuring just prior to administration. For example, in a study in which 5.0 mg of cyclobenzaprine immediate release tablet was administered and the mean plasma concentration of norcyclobenzaprine was 1.227 ng / mL at 24 hours, dnC _{met (24)} (norcyclo) ^* is ((1.227 ng / mL) / (5.0 mg)) = 0.245 ng / (mL mg) or 0.245 × 10 ⁻⁶ mL ⁻¹ . The dnC _{met (24)} ^* for multiple doses of cyclobenzaprine or amitriptyline is expected to be higher. In some embodiments, dnC _{met (24)} ^* is less than or equal to 1.0 ± 25% × 10 ⁻⁶ mL ^−1, less than or equal to 0.9 ± 25% × 10 ⁻⁶ mL ⁻¹ , 0.8 ± 25 % × 10 ⁻⁶ mL ⁻¹ or less, 0.7 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 0.6 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 0.5 ± 25% × 10 ⁻⁶ It is less than or equal to mL ⁻¹ , 0.4 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, or 0.3 ± 25% × 10 ⁻⁶ mL ⁻¹ or less. In some embodiments, dnC _{met (24)} ^* is less than or equal to 240 ± 25% × 10 ⁻⁹ mL ^−1, less than or equal to 220 ± 25% × 10 ⁻⁹ mL ⁻¹ , 200 ± 25% × 10 ⁻⁹ mL ^-1 or less, 180 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 160 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 140 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 120 ± 25% × 10 ^{− 6} mL ⁻¹ or less, 100 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 80 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 60 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 40 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 20 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, or 10 ± 25% × 10 ⁻⁹ mL ⁻¹ or less. In some embodiments, dnC _{met (24)} ^* is 9 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 9 ± 25% × 10 ⁻⁶ mL ⁻¹ or less, 7 ± 25% × 10 ⁻⁹ mL ^-1 or less, 6 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 5 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 4 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, 3 ± 25% × 10 ^{− 9} mL ⁻¹ or less, 2 ± 25% × 10 ⁻⁹ mL ⁻¹ or less, or 1 ± 25% × 10 ⁻⁹ mL ⁻¹ or less.

The ratio of the product of body mass and plasma concentration of norcyclobenzaprine to the dose of cyclobenzaprine administered is the dose- and body mass-normalized concentration of norcyclobenzaprine or dbmnC _met (norcyclo) ^* . The ratio of the product of body mass and plasma concentration of nortriptyline to the dose of amitriptyline administered is the dose- and body mass-normalized concentration of nortriptyline or dbmnC _met (nortrip) ^* . dbmnC _met ^* can be measured at various times after administration of the compound, either after a single dose or after multiple doses. dbmnC _met ^* can be measured either at fixed or variable time points, for example at a time point corresponding to C _max . For example, dbmnC _met ^* is 5 minutes after administration, 10 minutes after administration, 15 minutes after administration, 30 minutes after administration, 45 minutes after administration, 1 hour after administration, 2 hours after administration 3 hours after administration, 4 hours after administration, 5 hours after administration, 6 hours after administration, 7 hours after administration, 10 hours after administration, 11 hours after administration, or 12 hours after administration Can. In some embodiments, dbmnC _met ^* is 10 hours after administration, 11 hours after administration, 12 hours after administration, 13 hours after administration, 14 hours after administration, 15 hours after administration 16 hours, 17 hours after administration, 18 hours after administration, 19 hours after administration, 20 hours after administration, 21 hours after administration, 22 hours after administration, 23 hours after administration, 24 hours after administration It can be measured after or 36 hours after administration. DbmnC _met ^* or dbmn C _{met (24)} ^* at 24 hours: approximately 24 hours after or immediately following the last dose of the plasma concentration of the compound administered on a once daily dosing schedule, eg at bedtime dosing schedule It can be determined by measuring just prior to administration. For example, in a study where 5.0 mg of cyclobenzaprine immediate release tablet was administered and the mean plasma concentration of norcyclobenzaprine is 1.227 ng / mL at 24 hours and the average human body mass is 70 kg, dbmnC _{met (24)} ^{(Norushikuro) *} is 70kg × ((1.227ng / mL) / (5.0mg)) = 17.2 × 10 -6 kg · mL -1. It is expected that dbmnC _{met (24)} ^* for multiple doses of cyclobenzaprine or amitriptyline will be higher. In some embodiments, dbmnC _{met (24)} ^* is less than or equal to 1.0 ± 25% × 10 ⁻⁶ kg · mL ^−1, less than or equal to 0.9 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , 0 Less than or equal to 8 ± 25% × 10 ⁻⁶ kg · mL ^−1, less than or equal to 0.7 ± 25% × 10 ⁻⁶ kg · mL ^−1, less than or equal to 0.6 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ , 0.5 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 0.4 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, or 0.3 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ It is below. In some embodiments, dbmnC _{met (24)} ^* is less than or equal to 240 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ , 220 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 200 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 180 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 160 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, 140 ± 25% × 10 ⁻⁹ kg ^·· mL ^-1 or less, 120 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 100 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 80 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 60 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 40 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, 20 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, or 10 ± 25% It is less than or equal to 10 ^-9 kg · mL ^-1 . In some embodiments, dbmnC _{met (24)} ^* is less than ⁹ ± 25% × 10 ⁻⁹ kg · mL ⁻¹ , 9 ± 25% × 10 ⁻⁶ kg · mL ⁻¹ or less, 7 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 6 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 5 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 4 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 3 ± 25% × 10 ⁻⁹ kg · mL ⁻¹ or less, 2 ± 25% × 10 ⁻⁹ kg · mL ¹ or less, or 1 ± 25% × 10 ⁻⁹ kg · mL ¹ or less It is.
Excipient

In some embodiments, the compositions of the present invention are useful as pharmaceuticals. In some embodiments, the invention provides the use of a composition of the invention in the manufacture of a medicament. In some embodiments, it may be beneficial to include one or more excipients in the compositions of the present invention. One skilled in the art will appreciate that the choice of any one excipient may influence the choice of any other excipient. For example, selection of a particular excipient may render one or more additional excipients unusable, as some combinations of excipients may result in undesirable effects. One skilled in the art can determine empirically which additional excipients, if any, are included in the formulations of the present invention. For example, the compounds of the present invention may comprise at least one pharmaceutically acceptable carrier, such as solvents, fillers, binders, humectants, disintegrants, dissolution retarders, disintegrants, glidants, absorption enhancers, wetting agents. It can be combined with agents, solubilizers, lubricants, sweeteners or flavoring agents. "Pharmaceutically acceptable carrier" refers to any diluent or excipient that is compatible with the other ingredients of the formulation and not harmful to the recipient. Pharmaceutically acceptable carriers can be selected based on the desired route of administration, in accordance with standard pharmaceutical practice.
Extender

  In some embodiments, it may be beneficial to include a bulking agent in the compositions of the present invention. Bulking agents are commonly used in pharmaceutical compositions to increase the volume of the composition. Bulking agents are well known in the art. Thus, the bulking agents described herein do not constitute a comprehensive list, and are provided as merely exemplary bulking agents that can be used in the compositions and methods of the present invention.

Exemplary bulking agents can include carbohydrates, sugar alcohols, amino acids, and sugar acids. Bulking agents include mono-, di- or polysaccharide-carbohydrate, starch, aldose, ketose, amino sugar, glyceraldehyde, arabinose, lyxose, pentose, ribose, xylose, galactose, glucose, hexose, idose, mannose, Tulose, heptose, glucose, fructose, methyl aD-glucopyranoside, maltose, lactone, sorbose, erythrose, threose, trehalose, arabose, allose, allose, gulose, idose, talose, erythrose, ribulose, ribulose, psicose, tagatose, glucosamine, Galactosamine, arabinan, fructan, fucan, galactan, galacturonan, glucan, mannan, xylan, inulin, levan, fucoidan, carrageenan, Lactocarolose (galactocarolose), pectin, amylose, pullulan, glycogen, amylopectin, cellulose, microcrystalline cellulose, pustulan, chitin, agarose, keratin, chondroitin, dermatan, hyaluronic acid, xanthan gum, sucrose, Trehalose, dextran, lactose, alditol, inositol, sorbitol, mannitol, glycine, aldonic acid, uronic acid, aldaric acid, gluconic acid, isoascorbic acid, ascorbic acid, glucaric acid, glucuronic acid, gluconic acid, glucaric acid, galacturonic acid, These include, but are not limited to, mannuronic acid, neuraminic acid, pectic acid, corn starch, and alginic acid.
Disintegrant

In some embodiments, it may be beneficial to include a disintegrant in the compositions of the present invention. Disintegrants help to degrade solid compositions and facilitate delivery of the active pharmaceutical composition. Disintegrants are well known in the art. Some disintegrants are called super disintegrants because of their rapid properties and can be used as disintegrants in the context of the present invention. Thus, the disintegrants described herein do not constitute a comprehensive list, and are provided as merely exemplary disintegrants that can be used in the compositions and methods of the present invention. Exemplary disintegrants include crospovidone, microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, sodium starch glycolate, calcium carboxymethyl croscarmellose sodium, polyvinyl pyrrolidone, lower alkyl substituted hydroxypropyl cellulose, Indion 414, starch, Included are pregelatinized starch, calcium carbonate, gum, sodium alginate, and Pearlitol Flash®. Pearlitol Flash® (Roquette) is a mannitol-corn starch disintegrant specifically designed for orally dispersible tablets (ODT). Certain disintegrants have foaming properties.
Flow promoter

In some embodiments, it may be beneficial to include a glidant in the compositions of the present invention. Glidants help the powder to flow freely. Glidants are well known in the art. Thus, the glidants described herein do not constitute a comprehensive list, and are provided as merely exemplary glidants that can be used in the compositions and methods of the present invention. Exemplary glidants include colloidal silica (silicon dioxide), magnesium stearate, starch, talc, glycerol behenate, DL-leucine, sodium lauryl sulfate, calcium stearate, and sodium stearate.
lubricant

In some embodiments, it may be beneficial to include a lubricant in the compositions of the present invention. The lubricant helps to prevent aggregation of the components of the composition. Lubricants are well known in the art. Thus, the lubricants described herein do not constitute a comprehensive list, and are provided as merely exemplary lubricants that can be used in the compositions and methods of the present invention. Exemplary lubricants include calcium stearate, magnesium stearate, stearic acid, sodium stearyl fumarate, vegetable based fatty acids, talc, mineral oil, light oil, hydrogenated vegetable oils (eg peanut oil, cottonseed oil, sunflower) Oil, sesame oil, olive oil, corn oil, safflower oil, canola oil, coconut oil and soybean oil), silica, zinc stearate, ethyl oleate, ethyl laurate are included.
Sweetener

In some embodiments, it may be beneficial to include a sweetening agent in the compositions of the present invention. Sweetening agents help improve the mouthfeel of the composition by imparting sweetness to the composition. Sweetening agents are well known in the art. Thus, the sweeteners described herein do not constitute a comprehensive list, and are provided as merely exemplary sweeteners that can be used in the compositions and methods of the present invention. Exemplary sweetening agents include the saccharide families such as monosaccharides, disaccharides, trisaccharides, polysaccharides and oligosaccharides; sugars such as sucrose, glucose (corn syrup), glucose, invert sugar, fructose, maltodextrin and polydextrose Saccharin and its salts such as sodium and calcium salts; cyclamic acid and its salts; dipeptide sweeteners; chlorinated sugar derivatives such as sucralose and dihydrochalcone; sugar alcohols such as sorbitol, sorbitol syrup, mannitol, xylitol, hexa-resorcinol and the like And compounds selected from the combination thereof, but not limited thereto. Hydrogenated starch hydrolysates may be used, as well as potassium, calcium and sodium salts of 3,6-dihydro-6-methyl-1-1,2,3-oxathiazin-4-one-2,2-dioxide .
Flavor

In some embodiments, it may be beneficial to include flavorings in the compositions of the present invention. Flavoring agents help to improve the mouthfeel of the composition by imparting a more desirable taste to the composition. Flavoring agents are well known in the art. Thus, the flavoring agents described herein do not constitute a comprehensive list, and are provided as merely exemplary flavoring agents that can be used in the compositions and methods of the present invention. Exemplary flavoring agents include natural and / or synthetic (ie artificial) compounds such as peppermint, spearmint, wintergreen, menthol, cherry, strawberry, watermelon, grape, banana, peach, pineapple, apricot, pear, raspberry, May include lemon, grapefruit, orange, sweet potato, apple, lime, fruit punch, passion fruit, pomegranate, chocolate (eg, white, milk, dark), vanilla, caramel, coffee, hazelnut, cinnamon, combinations thereof, etc. Not limited to them.
Colorant

Coloring agents can be used to color-code the composition, for example to indicate the type and dosage of therapeutic agent in the composition. Colorants are well known in the art. Thus, the colorants described herein do not constitute a comprehensive list, and are provided as merely exemplary colorants that can be used in the compositions and methods of the present invention. Exemplary colorants include, but are not limited to, natural and / or artificial compounds such as FD & C colorants, natural fruit juice concentrates, pigments such as titanium oxide, silicon dioxide, and zinc oxide, combinations thereof, etc. I will not.
Combined treatment

  As mentioned above, the compositions and methods of the present invention may be used to treat PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorders, non-restorative sleep, chronic pain and anxiety disorders. Can. Any of the described treatment methods can be combined with psychotherapeutic interventions to improve the outcome of the treatment. Exemplary psychotherapeutic interventions include psychologic debriefing, cognitive behavioral therapy, and desensitization and reprocessing by eye movement, systematic desensitization, relaxation training, biofeedback, cognitive processing therapy, stress immune training, self. It is aimed at correction of memory of trauma or reduction of emotional response to memory of trauma, including assertive training, exposure therapy, combination of stress immune training and therapy, combination of exposure therapy and relaxation training, and cognitive therapy. In each case, the goal of the intervention includes either a correction of trauma memory or a reduction of emotional response to trauma memory. The desired result is generally an improvement in PTSD symptoms or a reduction in the appearance of symptoms, as evidenced by physiological responses, anxiety, depression, and a sense of alienation.

  In some embodiments of the present invention, the composition is a drug that can further reduce symptoms of PTSD, depression, fibromyalgia, traumatic brain injury, sleep disorder, non-restorative sleep, chronic pain, or anxiety disorder. Combined with Drugs include alpha-1-adrenergic receptor antagonists, beta adrenergic antagonists, anticonvulsants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and analgesics. Exemplary anticonvulsants include carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, and valproate. An exemplary alpha-1-adrenergic receptor antagonist is prazosin. Exemplary selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors include bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, escitalopram, fluvoxamine, milnacipran, paroxetine, sertraline, trazodone, And venlafaxine. Exemplary analgesics include pregabalin, gabapentin, acetaminophen, tramadol, and non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen sodium. Additional drugs that can be used in combination with the compositions of the invention include sodium oxybate, zolpidem, pramipexole, modafinil, temazepam, zaleplon, and armodafinil.

  It is to be understood that the embodiments of the present invention which have been described are merely illustrative of some of the applications of the principles of the present invention. Numerous modifications can be made by one skilled in the art based on the teachings presented herein without departing from the spirit and scope of the present invention.

  The following examples are described as representative of the present invention. As these and other equivalent embodiments will become apparent in light of the present disclosure, figures, and the appended claims, these examples are to be construed as limiting the scope of the present invention. You should not.

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注入速度（ｍＬ／秒）：５ 溶媒２による固定子洗浄時間（秒）：５
事前注入遅延（ミリ秒）：５００ 溶媒１による固定子洗浄時間（秒）：５
事後注入遅延（ミリ秒）：５００ 方法シリンジ（μＬ）：１００
ニードルギャップバルブ浄化（ｍｍ）：３
注記：溶媒１は、オートサンプラーすすぎ溶液番号１に対応し、溶媒２は、オートサンプラーすすぎ溶液番号２に対応する。したがって、バルブ洗浄、事後洗浄および固定子洗浄を、最初にメタノールで実施し、最後に移動相Ａで実施する。
オートサンプラーループ：１００μＬ、ステンレス鋼
注入体積：２０μＬ
注入温度：室温
プレカラムフィルタ：Ｓｕｐｅｌｃｏ Ｆｉｌｔｅｒ ０．５μｍ
カラム：供給者／製造者ＡＣＥ
ブランド／モデルＡＣＥ ３ Ｃ１８
長さ×幅（ｍｍ）３０×４．６
粒子（Ｐａｒｔｉｃｕｌｅ）の大きさ（μｍ）３
カラム温度：室温
保持時間（保持時間は、実施と実施の間で変わり得る。保持時間は二重注入なしに得た（例えば：ｃｏｈｅｓｉｖｅ））：
シクロベンザプリン：１．０５分
ノルシクロベンザプリン：１．１６分
内部標準Ａ：１．０５分
内部標準Ｂ：１．１５分
オートサンプラー実施時間：３．５０分（タイムセーバーオン）
取得時間：３．５０分
検出器パラメータ
供給源：ＴｕｒｂｏＩｏｎＳｐｒａｙ
分割比：適用できない
イオン化モード：正
ＡＰＩ ５０００（改変して、クロマトグラフィー条件、感度、または再現性を最適化することができる
補助ガス圧（ＧＳ２）：７０ｐｓｉ
ネブライザーガス圧（ＧＳ１）：５０ｐｓｉ
カーテンガス圧：４５ｐｓｉ
ＣＡＤガス：４
インターフェイスヒーター（Ｉｈｅ）：オン
ＴｕｒｂｏＩｏｎＳｐｒａｙ温度：４５０℃
イオンスプレー電圧（ＩＳＶ）：１８００
ステートファイルパラメータ：ＤＰ＝７０；ＥＰ＝１０；
（シクロベンザプリン）ＣＥ＝５５；ＣＸＰ＝１２
ステートファイルパラメータ：ＤＰ＝６５；ＥＰ＝１０；
（ノルシクロベンザプリン）ＣＥ＝４８；ＣＸＰ＝１２
ステートファイルパラメータ：ＤＰ＝７０；ＥＰ＝１０；
（内部標準Ａ）ＣＥ＝５５；ＣＸＰ＝１２
ステートファイルパラメータ：ＤＰ＝６５；ＥＰ＝１０；
（内部標準Ｂ）ＣＥ＝４８；ＣＸＰ＝１２
質量取得パラメータ：
分析物：ＭＲＭ滞留時間＝１５０ミリ秒；休止時間＝５ミリ秒
ＩＳ：ＭＲＭ滞留時間＝９０ミリ秒；休止時間＝５ミリ秒
シクロベンザプリン２７６．４（登録商標）２１５．２ａｍｕ
ノルシクロベンザプリン２６２．４（登録商標）２１５．２ａｍｕ
内部標準Ａ２７９．２（登録商標）２１５．１ａｍｕ
内部標準Ｂ２６５．４（登録商標）２１５．２ａｍｕ
積分パラメータ（変化させてピーク積分を最適化することができる）

較正パラメータ
ピーク特質：面積
較正等式：ｙ＝ｍｘ＋ｂ
較正回帰：線形
重み付け因子：１／Ｃ２
決定因子：ｒ２ Example 1
In order to study the metabolism of cyclobenzaprine, immediate release cyclobenzaprine HCl (Watson, bioequivalent to 5 mg of Flexeril) is administered to 10 healthy human subjects in 5 mg tablets for oral administration and cyclo Benzaprine and norcyclobenzaprine plasma concentrations 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3 hours 20 minutes, 3 hours 40 minutes, 4 hours, 4 hours 20 minutes, 4 hours 40 minutes, 5 hours, 5.5 hours, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, and 168 hours (1 week) The eye was measured (Table 2, Figures 1a and 1b). A high performance liquid chromatography method was also developed and validated to determine cyclobenzaprine and norcyclobenzaprine in human EDTA K ₃ plasma. The conditions used were as follows.
Mobile phase A (MPA) and autosampler rinse solution No. 1: Milli-Q type water / methanol (40/60), ammonium formate 5 mM, formic acid 0.1% (0.1: 100)
Mobile Phase B (MPB) and Autosampler Rinse Solution No. 2: Methanol (100%) Buffer Solution: Trizma® Base 500 mM, pH 11.0
Solution: Milli-Q type water / methanol (50/50)
Solvent delivery module: Hewlett Packard Series 1100, Agilent (Montreal, Canada)
Chromatography mode: reverse phase homogeneous solvent / gradient mode: gradient timetable program:

Mobile phase A flow rate: 1.000 mL / min Back pressure: 130 bar (approximately)
CTC PAL (HTC-xt) ^* (Stator washing station)
Injection macro:
Post-purification with valve purification solvent 1 with valve purification solvent 2 with needle immersion sample injection solvent 2 for sample pickup cleaning 1 Post purification with valve purification solvent 1 (Stator cleaning)
Auto sampler method:
Void volume (mL): 3 Valve cleaning time with solvent 2 (seconds): 2
Front volume (mL): 0 Post purification time with solvent 2 (seconds): 2
Rear volume (mL): 0 Valve cleaning time with solvent 1 (seconds): 3
Loading speed (μL / sec): 5 Post-purification time with solvent 1 (sec): 3
Pull-up delay (milliseconds): 3000 Stator cleaning: 1
Injection to LC VLV1 Stator cleaning delay (seconds): 120
Injection rate (mL / sec): 5 Stator cleaning time with solvent 2 (sec): 5
Pre-injection delay (milliseconds): 500 Stator cleaning time with solvent 1 (seconds): 5
Post injection delay (millisecond): 500 method Syringe (μL): 100
Needle gap valve purification (mm): 3
Note: Solvent 1 corresponds to autosampler rinse solution No. 1 and solvent 2 corresponds to autosampler rinse solution No. 2. Thus, valve wash, post wash and stator wash are performed first with methanol and finally with mobile phase A.
Autosampler loop: 100 μL, stainless steel injection volume: 20 μL
Injection temperature: Room temperature pre-column filter: Supelco Filter 0.5μm
Column: Supplier / Manufacturer ACE
Brand / model ACE 3 C18
Length x width (mm) 30 x 4.6
Particle size (μm) 3
Column temperature: room temperature hold time (hold time may vary between run and run time was obtained without double injection (eg: cohesive)):
Cyclobenzaprine: 1.05 minutes Norcyclobenzaprine: 1.16 minutes Internal standard A: 1.05 minutes Internal standard B: 1.15 minutes Autosampler Running time: 3.50 minutes (Time saver on)
Acquisition time: 3.50 minutes Detector parameter source: TurboIonSpray
Resolution ratio: not applicable ionization mode: positive API 5000 (auxiliary gas pressure (GS2) that can be modified to optimize chromatographic conditions, sensitivity, or reproducibility (70 psi)
Nebulizer gas pressure (GS1): 50 psi
Curtain gas pressure: 45 psi
CAD gas: 4
Interface heater (Ihe): On Turbo IonSpray temperature: 450 ° C
Ion spray voltage (ISV): 1800
State file parameters: DP = 70; EP = 10;
(Cyclobenzaprine) CE = 55; CXP = 12
State file parameters: DP = 65; EP = 10;
(Norcyclobenzaprine) CE = 48; CXP = 12
State file parameters: DP = 70; EP = 10;
(Internal standard A) CE = 55; CXP = 12
State file parameters: DP = 65; EP = 10;
(Internal standard B) CE = 48; CXP = 12
Mass acquisition parameter:
Analyte: MRM residence time = 150 milliseconds; rest time = 5 milliseconds IS: MRM residence time = 90 milliseconds; rest time = 5 milliseconds cyclobenzaprine 276.4 (registered trademark) 215.2 amu
Norcyclobenzaprine 262.4 (registered trademark) 215.2 amu
Internal standard A 279.2 (registered trademark) 215.1 amu
Internal standard B 265.4 (registered trademark) 215.2 amu
Integration parameters (can be varied to optimize peak integration)

Calibration parameter peak quality: area calibration equation: y = mx + b
Calibration regression: linear weighting factor: 1 / C2
Determinant: r2

Cyclobenzaprine and norcyclobenzaprine are extracted from aliquots of 0.200 mL of human EDTA K ₃ plasma using an automated liquid-liquid extraction procedure, then on a liquid chromatograph equipped with a tandem mass spectrometric detector Injected. The quantification was based on the peak area ratio of the analyte and their stable labeled internal standard. Weighted (1 / C2) linear regression was performed to determine the concentration of analyte. All regressions and figures presented in this validation report were generated by MDS Sciex Analyst version 1.4.2 and Thermo Electron Corporation Watson LIMS software, version 7.0.0.01b. Although the results of the method validation were acceptable, this means that human EDTA K over the range of 50 to 10000 pg / mL for cyclobenzaprine and 5 to 1000 pg / mL for norcyclobenzaprine ₃ demonstrates that it is suitable for determining cyclobenzaprine and norcyclobenzaprine in plasma. Cyclobenzaprine and norcyclobenzaprine in plasma were measured. Equilibrium receptor binding assays are performed on cell lines expressing expressed recombinant human receptors to obtain human serotonin 5-HT1a, 5-HT2a, 5-HT2b, 5-HT2c, 5-HT5a and 5-HT2. Determine the endogenous potency of cyclobenzaprine and norcyclobenzaprine against HT6 receptor, adrenergic alpha-1A, adrenergic alpha-2 (A, B, C), histamine H1, and muscarinic M1 and M2 receptors did. Selected receptors were analyzed for ligand-induced intracellular calcium mobilization.

表３：シクロベンザプリン：ノルシクロベンザプリン比

（実施例２） The amount of norcyclobenzaprine in plasma is unexpectedly high, and this finding is an improvement over the method we used compared to the literature method that did not detect norcyclobenzaprine Related to Furthermore, the half-life of norcyclobenzaprine was unexpectedly long. The t _max of cyclobenzaprine is calculated to be approximately 3.5 hours ( _AUCO -h h = 103.1 ± 35.8 ng · hr ^-1 mL), and the t _max of norcyclobenzaprine is approximately It was calculated to be 24.0 hours (AUC _{0-h h} = 169.5 ± 94.3 ng · hr · mL ⁻¹ ). Furthermore, the ratio of cyclobenzaprine to norcyclobenzaprine dropped more rapidly than expected, reaching a ratio of 1.1: 1 within 24 hours and down to 1: 2 by 72 hours (Table 3) ). This means that the half-life of norcyclobenzaprine is calculated to be approximately 73 hours (72.75 ± 27.71 hours), compared to approximately 31 hours (30.95 ± 7.18 hours) of cyclobenzaprine. Supported by a surprisingly long thing. These data indicate that norcyclobenzaprine remains in the system of interest long after most of the cyclobenzaprine has been excreted. Cyclobenzaprine and norcyclobenzaprine exhibited high affinity binding (K _i ) to the following receptors in vitro: 5-HT2a (5.2 and 13 nM) and 5-HT2c (5.2 And 43 nM), adrenergic α-1A (5.6 and 34 nM), α-2B (K _i = 21 and 150 nM) and α-2C (K _i = 21 and 48 nM); H1 (1.3 nM and 5. 6 nM); M1 (7.9 nM and 30 nM). Functionally, norcyclobenzaprine becomes an antagonist to 5-HT2a by Ca + mobilization (IC ₅₀ = 92 nM). Cyclobenzaprine is a functional antagonist for 5-HT2B (IC ₅₀ = 100 nM), which is consistent with the lack of association with any cardiac valve pathology. Cyclobenzaprine and norcyclobenzaprine are functional antagonists to 5-HT2c (IC ₅₀ = 0.44 μM and 1.22 μM) and α-2A (IC ₅₀ = 4.3 μM and 6.4 μM). In contrast, both CBP and nCBP were shown to be functional agonists for 5-HT1a (EC ₅₀ = 5.3 μM and 3.2 μM).
Table 2: Cyclobenzaprine and norcyclobenzaprine plasma concentrations

Table 3: Cyclobenzaprine: Norcyclobenzaprine Ratio

(Example 2)

  In order to ensure the accuracy of the data collected from in vivo studies, it was important to first develop an in vitro assay for assaying active pharmaceutical ingredients that can be used in the compositions and methods of the present invention . Therefore, we developed a LC-MS / MS analytical method for assaying cyclobenzaprine in beagle dogs, as described below.

The reagents were prepared as follows:
Methanol / UHQ water 20/80 v / v and 0.1% formic acid: 20 mL methanol (VWR) was mixed with 80 mL UHQ water (ADME) and 0.1 mL formic acid (Merck).
Carbonate buffer _{(Na 2 CO 3 0.1M / NaHCO} 3 0.1M50 / 50v / v (pH9.8): a _Na 2 CO 3 2.65 g, diluted with UHQ water 250 mL, 0.1 M of Na the .NaHCO ₃ 2.1g generating the ₂ CO ₃ and diluted with UHQ water 250 mL, was produced of NaHCO ₃ 0.1M. the final solution of 0.1M _Na 2 _CO 3 250 mL and 0.1M Prepared by mixing with 250 mL of NaHCO ₃ .

  Chromatographic peak areas were acquired and integrated using Analyst® 1.5.1 (Applied Biosystems) software. Watson® 7.2.0.03 (Thermo Electro Corporation) software was used for concentration calculation, data analysis, concentration data storage and statistical calculation. For statistical calculations on carryover, Excel® (2003) (Microsoft) was used.

これらの溶液を、調製した後に一定分量にし、−２０℃±５℃で保存し、使用後に各一定分量を廃棄した。
表５：希釈シクロベンザプリン溶液

表６：希釈内部標準溶液

Labeled cyclobenzaprine ([ ¹³ C, ² H ₃ ] cyclobenzaprine HCl) (Alsachim) was used as an internal standard (IS) of the cyclobenzaprine HCl (Alsachim) reference sample. Cyclobenzaprine and IS standard solutions were prepared in accordance with Tables 4 and 5 after being dissolved in appropriate volumes in an appropriate volume of solvent in a dark flask, taking into account the respective correction factors. The solution was vortex mixed and sonicated as needed until lysis was complete.
Table 4: Standard solution

These solutions were aliquoted after preparation, stored at -20 ° C. ± 5 ° C. and each aliquot discarded after use.
Table 5: Diluted cyclobenzaprine solution

Table 6: Diluted internal standard solution

表８：ブランクおよび二重ブランクの調製

表９：品質管理試料の調製

較正標準および品質管理試料を、毎日調製した。 Heparin lithium beagle dog plasma (also referred to herein as blank dog plasma) in which 20 μl of an appropriate dilution of cyclobenzaprine was previously centrifuged at 3500 rpm for about 5 minutes at 0 to 9 ° C. in a polypropylene microcentrifuge tube To 200 μl) was added as follows.
Table 7: Preparation of calibration standards

Table 8: Preparation of blanks and double blanks

Table 9: Preparation of quality control samples

Calibration standards and quality control samples were prepared daily.

表１１：自動サンプラーパラメータ

表１２：ポンプパラメータ

表１３：他のパラメータ

表１４：シクロベンザプリンと［^１３Ｃ，^２Ｈ_３］シクロベンザプリンのＨＰＬＣパラメータの比較

表１５：取得パラメータ

表１６：タンデム質量分析計の整調条件

The extraction procedure was performed as follows: 20 μl of 0.25 μg / mL [ ¹³ C, ² H ₃ ] cyclobenzaprine or 20 μl methanol for S0 was added to 200 μl blank dog plasma. To this solution 200 μl carbonate buffer was added and vortex mixed for 10 seconds. Thereafter, 1000 μl of hexane was added to this solution, mixed at 180 rpm for 10 minutes, and then centrifuged at 3500 rpm for 5 minutes at 0-9 ° C. The organic phase was transferred to a polypropylene tube and dried at 40 ° C. under a stream of nitrogen. 200 μl of methanol / water (20/80, v / v) and 0.1% formic acid were added to the dry residue, then sonicated for about 5 minutes and vortex mixed for 10 seconds. The mixture was then transferred to a polypropylene plate, centrifuged at 3500 rpm for 5 minutes at 0-9 ° C, stored at 0-9 ° C, and then injected into the LC-MS / MS system. Next, chromatography was performed using the parameters shown below.
Table 10: Chromatography Parameters

Table 11: Auto Sampler Parameters

Table 12: Pump Parameters

Table 13: Other parameters

Table 14: Comparison of HPLC parameters of cyclobenzaprine and [ ¹³ C, ² H ₃ ] cyclobenzaprine

Table 15: Acquisition parameters

Table 16: Tuning conditions for tandem mass spectrometers

表１８：Ｓ０ＳＩ試料の［^１３Ｃ，^２Ｈ_３］シクロベンザプリンＨＣｌ面積とＵＬＯＱ試料後に注入したブランク試料の内部標準面積の比較

表１９：逆算したイヌ血漿シクロベンザプリン濃度（ｎｇ／ｍＬ）および回帰パラメータ

表２０：イヌ血漿におけるシクロベンザプリンアッセイの実施内（反復性）、精度、および偏差

表２１：イヌ血漿におけるシクロベンザプリンアッセイの実施間（再現性）、精度、および偏差

（実施例３） The data collected during the development of the HPLC method is described in the following table. In particular, these data, comparing the peak area of cyclobenzaprine with the blank sample, indicate that there was no carryover of cyclobenzaprine in the continuous run (Table 17). These data also show that when the [ ¹³ C, ² H ₃ ] cyclobenzaprine HCl area of the blank sample is compared to the internal standard area, carryover is evident in the first run alone. However, at 0.1 interference%, the degree of carryover is negligible (Table 18).
Table 17: Comparison of cyclobenzaprine area of blank samples injected after lower limit of quantification (LLOQ) sample and upper limit of determination (ULOQ) sample

Table 18: Comparison of [ ¹³ C, ² H ₃ ] cyclobenzaprine HCl area of S0SI sample and internal standard area of blank sample injected after ULOQ sample

Table 19: Back calculated dog plasma cyclobenzaprine concentrations (ng / mL) and regression parameters

Table 20: Within-run (Repetitive), Accuracy, and Deviation of the Cyclobenzaprine Assay in Canine Plasma

Table 21: Between-run (reproducibility), accuracy, and deviation of cyclobenzaprine assays in dog plasma

(Example 3)

Using the LC-MS / MS analysis method described above, using the ± 25% acceptance criteria (except for the lower limit of quantitation (LLOQ) set at the ± 30% acceptance criteria), performing concentration response relationships, as well as deviations We verified the accuracy within and between the implementation. As mentioned above, cyclobenzaprine HCl and internal standard (IS) [ ¹³ C, ² H ₃ ] cyclobenzaprine HCl were used.

  The target LLOQ was set to 0.1 ng / mL to validate the LC-MS / MS method. Thus, the upper limit of quantification (ULOQ) corresponds to up to 500 times LLOQ, ie 50 ng / mL. In this method, a lithium heparin-treated plasma sample volume of 200 μl was required, and the extraction was liquid-liquid extraction with hexane. The extract was injected using an “Onyx monolithic Phenomenex C18 100 × 3.0 mm” column, using an HPLC system and AP14000® (Applied Biosystems) for MS / MS detection. We did not exclude any data from the calculation. The difference between the observed mean concentration and the nominal concentration was used to estimate the accuracy of the method. The coefficient of variation was used to estimate the accuracy of the method.

  Blank dog plasma was spiked with 4 concentrations of cyclobenzaprine HCl at LLOQ, 3 × LLOQ, 0.5 × ULOQ, and 0.8 × ULOQ. Concentration response relationships were determined from calibration standards for concentrations ranging from LLOQ to ULOQ in two different implementations. At least eight calibration points different from zero, prepared on the same day of analysis, were used for each calibration curve. One blank dog plasma sample (S0) that did not spike and two spiked with only the internal standard (S0SI) were analyzed with each calibration curve. The weighting factors were determined during qualification according to the results of the calibration curve regression fit. We used the simplest model that properly describes concentration-response relationships.

The target acceptance criteria include a 75% deviation of the calibration standard, the deviation being between ± 30.00% of the nominal value for LLOQ concentration levels and for nominal values of other concentration levels. It was in the range between ± 25.00%. The% deviation was measured as ((Cmeas-Cn) / Cn) x 100 (wherein Cmeas is the measured or back-calculated concentration and Cn is the nominal concentration). The calibration curve contains the lowest and highest levels, and the calibration standard is excluded from the final calibration curve only if the back-calculated deviation is not included within ± 25.00% of the nominal value Was done (except LLOQ and ULOQ). Using this method for each S0 and S0SI sample, the interference in the cyclobenzaprine retention time of the multiple reaction monitoring (MRM) trace specific for cyclobenzaprine is 30% of the cyclobenzaprine peak area of the LLOQ calibration standard. Should be less than 00% and for each S0 sample, the interference at the internal standard retention time of the MRM trace specific to the internal standard should be less than 2.00% of the internal standard peak area of S0SI is there. If these criteria are not met, conduct a validation study on 3x LLOQ virgin QC samples to assess the potential impact on measured concentrations of cyclobenzaprine. Conclusions should be drawn on the qualification of A summary of criteria or practices involving analytical batches is provided in Table 22 below.
Table 22: Acceptable criteria

  The accuracy and deviation within and between the performance of the assay method was tested in canine plasma in two different runs for each concentration level. For each concentration, QC samples were extracted in triplicate within the same run. The accuracy% was measured as (standard deviation / Cmean) × 100. All QC results were used for accuracy and mean deviation calculations, unless one was rejected due to a defined analytical problem. Accuracy was calculated for each concentration to meet the acceptance criteria, but the value should be <25.00% with the exception of LLOQ where <30.00% is acceptable (for each repeatability test In the reproducibility test, it was calculated at n = 12). The mean deviation was also calculated, but the value should be within ± 30.00% for LLOQ and within ± 25.00% for other acceptable concentrations (n = 6 for each repeatability test) Calculated, and in the reproducibility test, calculated at n = 12).

  One S0 sample was injected three times immediately after the last higher calibration standard (ULOQ) of at least one calibration curve. The MRM chromatograms were investigated for the presence of peaks at the retention times of cyclobenzaprine and IS, and the area of all peaks was measured. To meet the acceptance criteria, the peak area obtained at the cyclobenzaprine retention time of the MRM trace specific for each SO cyclobenzaprine was obtained for the first calibration standard (LLOQ) cyclobenzaprine Should be less than 30.00% of the peak area. The peak area obtained at the internal standard retention time of the MRM trace specific to each S0 internal standard should be less than 2.00% of the peak area obtained for the S0SI internal standard.

The cyclobenzaprine concentration was directly calculated using Watson® 7.2.0.03 from the peak area obtained after automated integration of the chromatogram by Analyst® 1.5.1. The concentration of QC samples was calculated by interpolating with a weighted calibration curve prepared under the same conditions and evaluated daily after automatic integration. When concentration results were acceptable, they were expressed as "ng / mL". Statistics (mean, SD, precision and deviation) were calculated using Watson® 7.2.0.03, with the exception of carryover calculated using Excel®.
(Example 4)

  To study the effects of the compositions and methods of the present invention, estimate the unchanged cyclobenzaprine plasma concentration levels after a single oral, sublingual or intravenous administration of cyclobenzaprine hydrochloride to female beagle dogs Protocol was developed. This protocol was designed as outlined in Table 23.

In the in vivo protocol, cyclobenzaprine HCl is tested with a calibration range of 0.1 to 50 ng / mL using the analysis method described above. This method requires a lithium heparin-treated plasma sample volume of 200 μl. The extraction is a liquid liquid extraction with hexane, using the extract, HPLC system and AP14000® (Applied Biosystems) for MS / MS detection, “Onyx monolithic Phenomenex C18 100 × 3.0 mm Using the column.
Table 23: In vivo study design

  In order to check the quality of the method in biological sample assays, virgin QC samples are prepared in duplicate at concentration levels of 3x LLOQ, 0.5x ULOQ and 0.8x ULOQ. Each assay series consists of one sample of non-spiked lithium heparin-treated blank beagle dog plasma (S0), two samples of lithium heparin-treated blank beagle dog plasma spiked with internal standard alone (S0SI), eight calibrations It consists of a standard, a minimum of six quality control (QC) samples that doubly cover three different concentrations of cyclobenzaprine distributed to the end of the whole series, and the biological sample to be assayed.

  Use the following criteria to validate the calibration curve: The 75% deviation of the calibration standard should be ± 25.00% of the nominal value, and should be ± 30.00% for LLOQ; lowest The level and maximum level must be included in the calibration curve; calibration standards should be excluded from the final calibration line if the back calculated concentration is not ± 25.00% of the nominal value It is. Perform additional investigations as needed using the following criteria: For each S0SI, the interference that may occur at the retention time of cyclobenzaprine is 30% of the cyclobenzaprine peak area of the LLOQ calibration standard. It should be less than 00%. If these criteria are not met, pre-dose and 3 × LLOQ QC samples to assess the potential impact on the measured concentrations of cyclobenzaprine and thus on the validation of the analytical performance. A survey should be conducted.

  A series is considered to be validated if at least 67% of the QC samples have a deviation range of ± 25.00% of the nominal concentration. Furthermore, any QC samples rejected should not correspond to the QC samples analyzed at the end of the series. Thus, only the concentration measured between the verified QC samples is considered to be verified. If dilution is required, add diluted QC to validate the dilution procedure. The dilution concentration is verified if at least one of the two QCs has a deviation range of ± 25.00% of the nominal concentration.

  The concentration of the sample was calculated automatically from the chromatogram using Watson® 7.2.0.03 after automatic integration with Analyst® 1.5.1, expressed as ng / mL. The mean plasma concentration is calculated using individual concentrations (when it can be calculated, ie n ≧ 2) and expressed with the corresponding standard deviation value and coefficient of variation (when it can be calculated ie n 3 3 In the case of (CV (%) = (SD / average) × 100). Individual plasma concentrations are tabulated at each dog and at scheduled sampling times. Concentrations below LLOQ are designated as "BLQ". All BLQ concentrations are replaced with 0 for calculation of descriptive statistics of concentration.

Pharmacokinetic analysis is performed using KINETICA® (version 4.3 (Thermo Electron Corporation)). Use an independent model (non-compartmental analysis). All BLQ values in the absorption phase are replaced by 0 prior to calculation of pharmacokinetic variables, except for BLQ values between assessable concentrations that are treated as missing values. The final BLQ value is ignored. Calculate the following pharmacokinetic parameters:
C _max (ng / mL): Maximum plasma concentration observed (for oral and sublingual administration).
T _max (h): time after administration until maximum plasma concentration is measured (for oral and sublingual administration).
AUC _t (ng / (mL × h)): area under the plasma concentration time curve from administration to the final concentration observed at time t measured by the trapezoidal rule.
AUC _inf (ng / mL × h): area under the plasma concentration time curve from administration by extrapolation of the final phase to infinity. This can also be expressed as AUCo _-∞ .
% AUC _extra : Percentage of extrapolated AUC calculated as (AUC _inf -AUC _t / AUC _inf ) x 100.
Elimination half-life calculated as T _1/2 ^* (h): ln 2 / K _el .
K _el ^* (1 / h): Estimated by linear regression of the logarithm of the final concentration as a function of time using Kinetica® software.
Cl and Cl / F ^* (L / h): apparent plasma clearance calculated as dose / AUC _inf .
_Vd and _Vd / F ^* (L): Apparent distribution volume calculated as Cl / _Kel .
Absolute bioavailability F% (%) = ((AUC by extravascular administration) / AUC by IV administration) × 100.
^* These parameters are calculated only if% _AUCextra is less than 20% and if the elimination phase contains 3 time points.
(Example 5)

  A protocol for the administration of cyclobenzaprine HCl in beagle dogs was designed to test the effects of the methods and compositions of the present invention described herein. This protocol is described below.

Test compound by oral administration by sublingual administration (SL) and intravenous (IV) administration to each dog using the 5 treated female dogs and administering them to the stomach via nasogastric tube (NG) To administer. There is at least a two week "wash-out" period between each type of administration. Blood samples are taken as follows.
Session 1: Oral administration

A single NG dose of 0.14 mg / kg (below volume 5 ml / kg and solution concentration 0.028 mg / mL) is administered. Blood samples are taken prior to dosing and then at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours after dosing (animals Total 12 blood samples per animal).
Session 2: Sublingual administration

After at least a two week wash-out period, the dog is sedated using propofol (6.5 mg / kg IV). Next, a single sublingual dose of 0.14 mg / kg is administered (below volume 0.056 mL / kg and solution concentration 2.5 mg / mL). Blood samples are taken before dosing and then 10, 20, 30, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after dosing (animals Total 12 blood samples per animal). Animals are not watered for 30 minutes after dosing.
Session 3: Intravenous administration

  After a wash-out period of at least 2 weeks, the dogs are dosed with a single IV dose of 0.14 mg / kg (volume 1 mL / kg, approximately 30 seconds of bolus, and below a solution concentration of 0.14 mg / mL). Blood samples are taken before dosing and then 10, 20, 30, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after dosing (animals Total 12 blood samples per animal).

  Blood sampling was designed to minimize animal pain and ensure the quality of the biological samples, and followed the basic procedure commonly used in studies conducted in dogs. Serial blood samples (approximately 5 mL of one tube) are collected from the jugular vein using a vacuum tube containing lithium heparin. After sealing each tube, blood samples are manually mixed and stored on ice until centrifugation (within 30 minutes of sampling). Samples are centrifuged at 1500 g for 10 minutes at 4 ° C. The resulting whole plasma from each tube is immediately transferred to appropriately labeled polypropylene tubes (at least three aliquots of 500 μl each of plasma), stored upright at approximately -80 ° C, and bioanalytical Protect from light until you do.

  The dogs are fasted overnight and each dose is given and dogs are fed 4 hours after each treatment. Cyclobenzaprine HCl is administered at 0.14 mg / kg for each of the three administration routes (PO, sublingual and IV). Potassium phosphate buffer (pH 7.4) is used as the vehicle in each of the three routes.

Female beagle dogs weighing 12-18 kg obtained from HARLAN or CEDS are used in these trials. The dogs are housed in groups in a kennel with free access to food and water at natural light and controlled ambient temperature 18 ± 3 ° C. During the pharmacokinetic phase, dogs are kept alone on a floor area of approximately 1 m ² or 2 m ² . During this phase, the animal husbandry is maintained at a controlled ambient temperature of 18 ± 3 ° C., under artificial light, from 7:00 to 19:00 (12 hours).
(Example 6)

表２５：リン酸緩衝溶液ｐＨ７．４への溶解（体積＝１００ｍＬ）

The solubility of cyclobenzaprine HCl is tested both in purified water (Table 24) and in an aqueous solution containing monobasic potassium phosphate (KH ₂ PO ₄ ) and NaOH to adjust the solution to pH 7.4. did. The (KH ₂ PO ₄ ) solution was prepared according to current USP (USP 34) (Table 25). Briefly, 50 mL of 0.2 M monobasic potassium phosphate (KH ₂ PO ₄ ) was mixed with 39.1 mL of 0.2 M NaOH and water was added to bring the solution to a final volume of 200 mL. During the test, the change in pH of the solution was also measured after each addition. The test was performed on 100 mL of sample and 5 g of cyclobenzaprine HCl was added each time to an initial aliquot of 10 g. Each pH value was measured only after the added amount of cyclobenzaprine HCl had completely dissolved. The measured values are recorded in the following table. The solubility data for cyclobenzaprine HCl (30 g per 100 g water) reported in the literature were consistent with using aqueous KH ₂ PO ₄ (pH 7.4) as solvent.
Table 24: Dissolution in purified water (volume = 100 mL)

Table 25: Dissolution in phosphate buffer solution pH 7.4 (volume = 100 mL)

According to the protocol for the preclinical studies mentioned above, the solution administered for the sublingual route had to be at a concentration of 2.5 mg / mL (solvent: KH ₂ PO ₄ aqueous solution, pH 7.4 as described above) ). The volume of cyclobenzaprine HCl solution administered was 0.056 mL / kg. In search of the available literature and in anticipation of collecting data after setting up the pre-formulation, we assumed an average weight of 10 kg for each dog. Thus, the amount of sublingually administered cyclobenzaprine HCl solution was 0.56 mL, corresponding to 1.4 mg cyclobenzaprine HCl.

  In order to simulate the sublingual ambient pH of the animals, artificial saliva was prepared with some modifications, taking into account the standard procedures of the available literature (see, for example, UNI EN 12868: 2002). Briefly, 4.2 g of sodium bicarbonate, 500 mg of sodium chloride, 200 g of potassium carbonate and 30 mg of sodium nitrite were dissolved in 900 mL of purified water while stirring with a magnetic stirrer. The final pH of the solution was about pH 8 to pH 9, which was acidified using lactic acid to approximately pH 5.5.

表２７：人工唾液におけるシクロベンザプリンＨＣｌ錠剤（対照：塩基性化剤は欠如）のｐＨ測定

0.56 mL of cyclobenzaprine HCl solution corresponding to the dose administered to the dog to account for different volumes of saliva that may be present under the tongue of the animal (solvent: H ₂ O as above; basic An agent: KH ₂ PO ₄ aqueous solution, pH 7.4) was added to 1 mL, 3 mL and 5 mL of saliva, and the pH value was measured as described in Table 26. Instead of cyclobenzaprine HCl alone, a formulation without basifying agent was added to the saliva and the same pH measurement was performed (Table 24).
Table 26: pH measurement of cyclobenzaprine HCl solution in artificial saliva

Table 27: pH measurement of cyclobenzaprine HCl tablets (control: no basifying agent) in artificial saliva

（実施例７） As mentioned above, K ₂ HPO ₄ was added to the tablet formulation in order to increase the sublingual pH after administration of the tablets to pH 7.4, which is a pH value as similar as possible to the aqueous KH ₂ PO ₄ solution. The amount was determined by performing a pH trial on a solution obtained by dissolving formulated tablets lacking K ₂ HPO ₄ basifying agent in artificial saliva. By adding _K 2 _HPO 4 1.05 mg to control formulation _(K 2 HPO ₄ basifying agents lack), to give the results shown in Table 28.
Table 28: pH measurement of cyclobenzaprine HCl tablets (containing basifying agent) in artificial saliva

(Example 7)

An exemplary composition formulated for sublingual administration is a sublingual tablet designed to disintegrate rapidly under the tongue. To develop this type of composition, the galenic properties of cyclobenzaprine HCl were studied. Solubility studies have confirmed that a slightly basic medium (eg, aqueous KH ₂ PO ₄ , pH 7.4 as described above) is a possible solvent for cyclobenzaprine HCl.

The specifications of the sublingual dosage form are not defined by the Pharmacopoeia, and therefore, in order to obtain tablets called oral dispersible forms, which have a disintegration time according to the USP specification (disintegrate in less than 30 seconds), We chose preliminary storage. This specification is one target of the formulation but not an essential specification. Based on this feature, disintegrants (crospovidone) and very delicious disintegrants (Pearlitol Flash) were selected. Based on the aforementioned characteristics of the aqueous KH ₂ PO ₄ solution, pH 7.4, a stoichiometric ratio of K ₂ HPO ₄ was introduced into one of the pre-formulations as a basifying agent. In addition, a formulation lacking the basifying agent was also produced. For each formulation procedure, batches of cyclobenzaprine HCl obtained from two different suppliers were tested in order to select the best batch for further testing. In both cases, the final mixture was obtained by dry mixing and adding the lubricant only in the final mixing step. The progressive dilution method was applied due to the low concentration of active ingredient.

表３６：塩基性化剤を含有するシクロベンザプリンＨＣｌ製剤の分析結果

＊予備分析条件を、これらの予備治験に適用した；ＴＢＤ：未決定 The tableting phase was carried out on a GP1 tableting machine equipped with a 4 mm punch. The choice of punch considered the mode of administration, as the choice of punch affects both the diameter and the shape of the tablet to match the sublingual route and transmucosal absorption. The final mixture and the corresponding tablets were tested for all of the standard parameters recorded here below. _Two formulations containing K ₂ HPO ₄ as a basifying agent were prepared as described in Table 35. These formulations differed only in that they used cyclobenzaprine HCl obtained from different suppliers. The analysis results of each formulation are summarized in Table 36.
Table 35: Cyclobenzaprine HCl formulations containing basifying agents

Table 36: Analysis of cyclobenzaprine HCl formulations containing basifying agents

* Preliminary analysis conditions were applied to these preliminary trials; TBD: Not determined

表３８：塩基性化剤を含有するシクロベンザプリンＨＣｌ製剤の分析結果

＊予備分析条件を、これらの予備治験に適用した；ＴＢＤ：未決定 Formulations lacking the K ₂ HPO ₄ basifying agent were prepared as described in Table 37 below. The analysis results of these formulations are described in Table 38.
Table 37: Cyclobenzaprine HCl formulation lacking basifying agent

Table 38: Analysis of cyclobenzaprine HCl formulations containing basifying agents

* Preliminary analysis conditions were applied to these preliminary trials; TBD: Not determined

Both formulations were identified as appropriate based on the results of distribution, assay and content uniformity.
(Example 8)

＊室温で保存した試料で得られたデータ
表４０：塩基性化剤を含まないシクロベンザプリンＨＣｌ製剤、５０℃で３０日間

＊室温で保存した試料で得られたデータ
表４１：２つの製造者から得たシクロベンザプリンＨＣｌ活性成分

＊室温で保存した試料で得られたデータ Prototypes A, B, C, D were maintained under stress conditions of 50 ° C. for 30 days in order to evaluate the stability of the aforementioned formulations. The results are set forth in Tables 39 and 40 below, respectively. Cyclobenzaprine HCl without excipients, obtained from each manufacturer, was also tested over the course of 15 days as shown in Table 41. In summary, the formulation was stable, especially when considering high stress storage conditions. And formulations containing K ₂ HPO ₄ basifying _agents, differences in formulation K 2 HPO ₄ basifying agent is lacking, was minimal.
Table 39: Cyclobenzaprine HCl formulation containing basifying agent, 30 days at 50 ° C.

* Data obtained with samples stored at room temperature Table 40: Cyclobenzaprine HCl formulation without basifying agent, 30 days at 50 ° C

* Data obtained with samples stored at room temperature Table 41: Cyclobenzaprine HCl active ingredient obtained from two manufacturers

* Data obtained with samples stored at room temperature

表４３：未微粒子化シクロベンザプリンＨＣｌ製剤（Ｋ_２ＨＰＯ_４塩基性化剤を含有する）の分析

As mentioned above, micronized cyclobenzaprine HCl supplied by Dipharma and non- micronized cyclobenzaprine HCl supplied by Sifavitor are equivalent with respect to their drug discovery activity and properties. To confirm this conclusion, additional clinical trials were designed using the unmicronized cyclobenzaprine HCl supplied by Dipharma for both formulations (with and without the K ₂ HPO ₄ basifying agent) did. This formulation was made to compare the same features of unmicronised cyclobenzaprine HCl supplied by two different manufacturers (Table 42). The formulation was then analyzed as shown in Table 43 and compared to the previous formulation.
Table 42: Non-particulated cyclobenzaprine HCl formulation (containing basifying agent)

Table 43: Analysis of unmicroparticulated cyclobenzaprine HCl formulation (containing K ₂ HPO ₄ basifying agent)

表４５：未微粒子化シクロベンザプリンＨＣｌ製剤（対照：塩基性化剤が欠如している）の分析

Micronized cyclobenzaprine HCl was replaced with non-microparticulate cyclobenzaprine HCl to replicate the control cyclobenzaprine HCl formulation described above (lacking basifying agent) (Table 44). The formulation was then analyzed as shown in Table 45 and compared to the previous formulation lacking the K ₂ HPO ₄ basifying agent.
Table 44: Non-particulated cyclobenzaprine HCl formulation (lacking basifying agent)

Table 45: Analysis of unparticulated cyclobenzaprine HCl formulation (control: lack of basifying agent)

In summary, Dipharma batches of unmicroparticulated cyclobenzaprine HCl demonstrated good distribution and performance for the tested formulations (e.g. the disintegration time in tablet form was particularly short). The Dipharma batch of micronized cyclobenzaprine HCl, except for some static phenomena typical of micronized powders, demonstrated good distribution and performance for the tested formulations. The Sifavitor batch of non-particulate cyclobenzaprine HCl demonstrated good distribution and performance for the tested formulations.
All analytical results recorded in Example 8 and referring to the previously recorded formulations were obtained by performing according to the following analytical conditions.
Assay analyzer: HPLC JASCO with autosampler AS-1555, pump PU-1580 and detector UV-2075 Plus
Analytical column: ALLTIMA C ₁₈ 5 μm 150 × 4.6 mm or equivalent Mobile phase: 49.8% water 25% methanol 25% acetonitrile 0.2% methanesulfonic acid mobile phase corrected to pH 3.60 ± 0.10 with diethylamine Flow rate: 1.5 ml / min Wavelength: 240 nm
Injection volume: 10 μl
Temperature: 25 ° C
Length of acquisition time: 8 minutes Solvent: 50% methanol 50% phosphate buffer: (6.80 g / l potassium dihydrogen phosphate and 1.57 g / l sodium hydroxide dissolved in water, necessary Correct to pH 7.40 ± 0.10 with 1N sodium hydroxide)
Cyclobenzaprine retention time: about 5.0 minutes Preparation of product standard: Weigh about 20 mg of cyclobenzaprine HCl reference (or effect) standard into a 50 mL volumetric flask, add 40 ml solvent, and over 5 minutes Sonicate and dilute to volume with solvent. Transfer 2.5 mL of this solution to a 10 mL volumetric flask and dilute to volume with solvent (concentration of cyclobenzaprine HCl = about 100 μg / mL).
Sample preparation (powder): Weigh about 160 mg of cyclobenzaprine HCl powder into a 100 mL volumetric flask, add 70 mL of solvent, stir with magnetic stirrer for 10 minutes, sonicate for 5 minutes, define with solvent Dilute to volume. After filtration through a syringe filter with a 0.45 μm hydrophilic PVDF membrane, it is injected. The concentration of cyclobenzaprine HCl is 100 μg / mL].
Sample preparation (tablets): Weigh 10 cyclobenzaprine HCl tablets into a 100 mL volumetric flask, add 80 mL solvent, stir with magnetic stirrer for 10 minutes, sonicate for 5 minutes, prescribe with solvent Dilute to volume. Transfer 4 mL to a 10 mL volumetric flask and dilute to volume with solvent. After filtration through a syringe filter with a 0.45 μm hydrophilic PVDF membrane, it is injected. [The concentration of cyclobenzaprine HCl is 100 μg / mL].
Purity Analyzer: HPLC JASCO with autosampler AS-1555, pump PU-1580, and detector UV-2075 Plus
Analytical column: ALLTIMA C ₁₈ 5 μm 150 × 4.6 mm or equivalent Mobile phase: 59.8% water 20% methanol 20% acetonitrile 0.2% methanesulfonic acid mobile phase corrected to pH 3.60 ± 0.10 with diethylamine Flow rate: 2.0 ml / min Wavelength: 240 nm
Injection volume: 20 μl
Temperature: 25 ° C
Length of acquisition time: 60 minutes Solvent: methanol retention time: about 12.0 minutes Retention time of relevant substances: dibenzosuberenone (impurity 1): about 56.0 minutes carbinol (impurity 2): about 6.0 Minute amitriptyline (impurity 4): Preparation of the relevant substance standard about 15.0 minutes (for known and unknown impurities): about 10 mg cyclobenzaprine HCl reference (or action) standard and about 10 mg cyclobenzaprine HCl impurity 1 2, 4 Reference (or working) standard is weighed into a 100 mL volumetric flask, 80 ml of methanol is added, sonicated for 10 minutes, and diluted to volume with methanol.
Transfer 1.0 mL of this solution to a 100 ml volumetric flask and dilute to volume with solvent. The concentration of impurities is 1 μg / mL corresponding to 0.1%.
Sample preparation: Weigh exactly 4 cyclobenzaprine HCl tablets into a 10 mL volumetric flask, add 5 mL of solvent, sonicate for 10 minutes, and dilute to volume with solvent. After filtration through a syringe filter with a 0.45 μm hydrophilic PVDF membrane, it is injected. The concentration of cyclobenzaprine HCl is about 1000 μg / mL.

表４７：塩基性化剤が欠如したシクロベンザプリンＨＣｌ製剤

Starting from all data collected in the formulation setting, further batches of formulations with and without basifying agent were produced. As a final step in drug development, large test batches were manufactured according to the formulations recorded in Tables 46 and 47.
Table 46: Cyclobenzaprine HCl formulations containing basifying agents

Table 47: Cyclobenzaprine HCl formulation lacking basifying agent

Starting from a cyclobenzaprine HCl formulation containing a basifying agent, additional formulations were manufactured. A coating of this was obtained using a coating mixture that also contained a basifying agent, as described in Table 48.
Table 48: Cyclobenzaprine HCl formulations containing basifying agents (coated formulations)

The time 0 data obtained from the stability studies with the large inspection batches of different packaging materials are recorded in Table 49.
Table 49: Stability studies, time 0 data

The samples are stored at 40 ° C. and 50 ° C. and analyzed after 1, 2, 3 and 4 weeks in order to study the stress stability of batches lacking the basifying agent. The data as of week 1 is recorded in Table 50.
Table 50: Stability studies, week 1, no basifying agent

All of the analyzes performed starting from the large test batch were performed according to the following optimized and verified conditions.
Purity Analyzer: HPLC JASCO with autosampler AS-2055, PU-2080, and detector Diode Array MD 2010 Plus
Analytical column: SYMMETRY C18 5 μm 250 × 4.6 mm or equivalent Mobile phase: 25% methanol, 25% acetonitrile, 50% butylamine buffer / CH ₃ COOH (10 ml of 99.5% butylamine in 950 ml of water, glacial acetic acid Adjust to pH 6.20 ± 0.10 with and dilute to 1 L volume with water)
Flow rate: 1.5 mL / min Wavelength: 239 nm
Injection volume: 10 μl
Temperature: 28 ° C
Length of acquisition time: 35 minutes Solvent: Mobile phase retention time: Impurity A (carbinol) about 6 ', Impurity B (amitryptyline) about 14', Impurity C (dibenzosuberenone) about 29 ', cyclobenzaprine HCl about 11 '

For preparation of related standards (for known and unknown impurities): about 10 mg of cyclobenzaprine HCl reference (or working) standard, and about 10 mg of cyclobenzaprine HCl impurity A, B and C references (or working) standard Is weighed into a 100 mL volumetric flask, 5 mL of acetonitrile is added, then 75 mL of solvent is added, sonicated for 5 minutes, and diluted to volume with solvent.
Transfer 1.0 mL of this solution to a 50 ml volumetric flask and dilute to volume with solvent to bring the final concentration of impurities to 2 μg / mL.
LOQ level: Transfer 1.0 mL of the final solution to a 10 ml volumetric flask and dilute to volume with solvent to bring the concentration of impurities to 0.2 μg / mL.
For sample preparation: Accurately weigh 10 cyclobenzaprine HCl tablets into a 25 mL volumetric flask (or 20 cyclobenzaprine HCl tablets into a 50 mL volumetric flask), 20 mL solvent (or 40 mL) Add, sonicate for 5 minutes, and dilute to volume with solvent. After filtration through a syringe filter with a 0.45 μm hydrophilic PVDF membrane, it is injected. The concentration of cyclobenzaprine HCl is about 1000 μg / mL.
Assay Analyzer: HPLC JASCO with autosampler AS-1555, pump PU-1580, and detector UV-2075 Plus
Analytical column: ALLTIMA C ₁₈ 5 μm 150 × 4.6 mm or equivalent Mobile phase: 49.8% water 25% methanol 25% acetonitrile 0.2% methanesulfonic acid mobile phase corrected to pH 3.60 ± 0.10 with diethylamine Flow rate: 1.5 ml / min Wavelength: 240 nm
Injection volume: 10 μl
Temperature: 25 ° C
Length of acquisition time: 8 minutes Solvent: 50% methanol 50% phosphate buffer (6.80 g / l potassium dihydrogen phosphate and 1.57 g / l sodium hydroxide are dissolved in water, if necessary (Adjusted to pH 7.40 ± 0.10 with 1N sodium hydroxide)
Cyclobenzaprine retention time: about 5.0 minutes Preparation of product standard: Weigh about 20 mg of cyclobenzaprine HCl reference (or effect) standard into a 50 mL volumetric flask, add 40 ml solvent, and over 5 minutes Sonicate and dilute to volume with solvent. Transfer 2.5 mL of this solution to a 10 mL volumetric flask and dilute to volume with solvent to equal the concentration of cyclobenzaprine HCl to about 100 μg / mL.
Sample preparation (powder): Weigh about 160 mg of cyclobenzaprine HCl powder into a 100 mL volumetric flask, add 70 mL of solvent, stir with magnetic stirrer for 10 minutes, sonicate for 5 minutes, define with solvent Dilute to volume. In order to make the concentration of cyclobenzaprine HCl 100 μg / mL, it is injected after being filtered through a syringe filter having a hydrophilic PVDF membrane of 0.45 μm.
Sample preparation (tablets): Weigh 10 cyclobenzaprine HCl tablets into a 100 mL volumetric flask, add 80 mL solvent, stir with magnetic stirrer for 10 minutes, sonicate for 5 minutes, prescribe with solvent Dilute to volume. Transfer 4 mL to a 10 mL volumetric flask and dilute to volume with solvent. In order to make the concentration of cyclobenzaprine HCl 100 μg / mL, it is injected after being filtered through a syringe filter having a hydrophilic PVDF membrane of 0.45 μm.
(Example 9)

As noted in Example 4, a study was designed to evaluate the efficacy of the compositions and methods of the present invention. The study utilized beagle dogs and given cyclobenzaprine HCl orally, sublingually or intravenously. Next, pharmacokinetic parameters were calculated. The outline of the study design is as follows.
Test substance: Cyclobenzaprine hydrochloride Administration route: oral (PO), sublingual and intravenous (IV)
Species: Beagle dog Sex: Female matrix: Plasma vehicle: KH ₂ PO ₄ aqueous solution adjusted to pH 7.4 with NaOH Dose: 0.14 mg / kg (equivalent to a dose of approximately 10 mg for a 70 kg human)
Formulation concentration: PO: 0.028 mg / mL; Sublingual: 2.5 mg / mL; IV: 0.14 mg / mL
Administration volume: PO: 5 mL / kg; Sublingual: 0.056 mL / kg; IV: 1 mL / kg

  Blood was drawn fasted for all three routes of administration. In PO administration, blood is collected at 0 hour (before administration) and at 0.5 hour, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours and 24 hours of administration. did. For sublingual and IV administration, blood was collected before administration and at 10 minutes, 20 minutes, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 24 hours after administration. . The analysis of cyclobenzaprine was performed substantially as described above. Briefly, this method involved liquid-liquid extraction with hexane. The extract was injected using an “Onyx monolithic Phenomenex C18 100 × 3.0 mm” column, using an HPLC system and an API 4000® for MS / MS detection (Applied Biosystems). This method was linear from 0.1 ng / mL to 50 ng / mL for cyclobenzaprine in dog plasma. Quality control samples were prepared at 0.3, 25 and 40 ng / mL for cyclobenzaprine in dog plasma. The results obtained from the analysis of quality control samples were within the tolerance limits defined in the protocol, thus validating the concentrations measured in plasma samples.

Intravenous (IV) administration of cyclobenzaprine HCl solution containing a basifying agent provides a surprising dynamic range in plasma concentration-time profiles and bioavailability of cyclobenzaprine administered by nasogastric tube Was surprisingly low. In the past beagle experiments, 2 mg / kg of cyclobenzaprine was administered to beagle (6.7-8.2 kg) with radiolabelling (Hucker, 1978 Drug Metabolism)
and Disposition 6 (6): 659). The doses are expressed as the free base and therefore have to be adjusted by the MW of 275 g / mol of free base / Mw 312 g / mol of the HCl salt. Therefore, 1.76 mg / kg of cyclobenzaprine HCl was administered. Cyclobenzaprine was administered by saline solution for intravenous (IV) administration or by gelatin capsule for oral (PO) administration. In the Hucker study, plasma levels of cyclobenzaprine were measured by recovering a radioactive equivalent of ¹⁴ C-labeled cyclobenzaprine, thus plasma levels were determined with a specific value (μg / ml) of cyclobenzaprine It was "equivalent." According to this method, beagle orally administered 1.76 mg / kg of cyclobenzaprine HCl was 0.72 μg / ml [equivalent] (0.5 hour time), 1.14 μg / ml [equivalent] (1 hour) , 1.46 μg / ml [equivalent] (2 hours), 0.92 μg / ml [equivalent] (4 hours), 0.58 μg / ml [equivalent] (6 hours), 0.10 μg / ml [equivalent] (24 Dogs with an hourly plasma level and administered by intravenous infusion of 2 mg / kg of cyclobenzaprine in saline, 0.43 μg / ml [equivalent] (0.5 hours), 0.53 μg / Ml [equivalent] (1 hour), 0.60 μg / ml [equivalent] (2 hours), 0.55 μg / ml [equivalent] (4 hours), 0.45 μg / ml [equivalent] (6 hours), 0 Plasma level of 12 μg / ml [equivalent] (24 hours) It had. In our beagle study, the dose was 0.14 mg / kg, approximately 1 / 12.6 of the administration of the Hucker study. Assuming dose proportionality, Hucker's data would be equivalent to a 0.14 mg / kg dose of cyclobenzaprine HCl, assuming dose proportionality, simply to compare the pharmacokinetic profile of the Hucker's study with ours' study. It was adjusted. They are shown in Table 51.
Table 51: Comparison of pharmacokinetics

  By comparison, Hucker's PO bioavailability with gelatine capsules, adjusted for dose and dose proportionality to our study, is the bioavailability of cyclobenzaprine oral solution via nasogastric tube (NG) It became clear that it was considerably higher (peak of 115.9 ng / ml at 2 hours) than peak of 0.41 ng / ml at 1 hour. The profile of cyclobenzaprine administered IV by Hucker is relatively flat from 0.5 h to 6 h, which, when adjusted for dose and dose proportionality to our study, is 0. 0. From 34.1 ng / ml at 5 hours to 47.6 ng / ml (2 hours) and then to 35.7 ng / ml, our profile is dynamic over that period, It dropped from 52.3 ng / ml to 3.4 ng / ml. Although Hucker did not measure plasma levels at 0.167 hours or 0.33 hours, in our study these values are at the highest plasma levels, indicating an even more dynamic range. Hucker did not study sublingual administration.

^＊中央値
^＊＊ＣｌおよびＶｄは、ＰＯおよび舌下経路のＣｌ／ＦおよびＶｄ／Ｆである
ＮＡ：適用されず
表５３：シクロベンザプリンＨＣｌの経口投与後に測定したシクロベンザプリン血漿濃度（ｎｇ／ｍＬ）

表５４：シクロベンザプリンＨＣｌの舌下投与後に測定したシクロベンザプリン血漿濃度（ｎｇ／ｍＬ）

ＢＬＱ：定量限界（０．１ｎｇ／ｍＬ）未満
イタリック体：範囲外（５０ｎｇ／ｍＬ）：指標のために与えられた値
表５５：シクロベンザプリンＨＣｌのＩＶ投与後に測定したシクロベンザプリン血漿濃度（ｎｇ／ｍＬ）

ＢＬＱ：定量限界（０．１ｎｇ／ｍＬ）未満
表５６：シクロベンザプリンＨＣｌの投与後のシクロベンザプリン薬物動態パラメータ

^＊ＣｌおよびＶｄは、ＰＯおよび舌下経路のＣｌ／ＦおよびＶｄ／Ｆである
イタリック体：％ＡＵＣｅｘｔｒａ＞２０％：指標のために与えられた値
ＮＣ：算出されず
ＮＡ：適用されず Sublingual administration of cyclobenzaprine HCl surprisingly resulted in improved pharmacokinetic properties and bioavailability compared to PO administration (Table 52, Figures 2 and 3; PO, individual, sublingual SL) and IV data: Tables 53-56). In particular, the _Cmax of cyclobenzaprine was significantly higher when administered sublingually at approximately 0.48 ng / mL (PO) to approximately 137 ng / mL (SL). Also, T _max decreased from 1 hour to 10 minutes and bioavailability increased from approximately 3.8% to 292%. Similar to standard practice, the bioavailability of IV administration was considered 100%. We believe that a possible explanation for sublingual bioavailability can be explained by taking IV measurements after the true C _max value of IV was to be recorded. Nevertheless, the bioavailability of PO and sublingual administration is almost 77 times higher.
Table 52: Mean ± SD plasma pharmacokinetic parameters

^* Median
^** Cl and Vd are PO and Cl / F and Vd / F of the sublingual route NA: not applicable Table 53: Cyclobenzaprine plasma concentrations (ng / mL) measured after oral administration of cyclobenzaprine HCl

Table 54: Cyclobenzaprine plasma concentrations (ng / mL) measured after sublingual administration of cyclobenzaprine HCl

BLQ: less than the limit of quantification (0.1 ng / mL) Italic: out of range (50 ng / mL): value given for the indicator Table 55: cyclobenzaprine plasma concentration measured after IV administration of cyclobenzaprine HCl ( ng / mL)

BLQ: less than the limit of quantification (0.1 ng / mL) Table 56: Cyclobenzaprine pharmacokinetic parameters after administration of cyclobenzaprine HCl

^* Cl and Vd are PO and the sublingual pathway Cl / F and Vd / F italics:% AUCextra> 20%: value given for the indicator NC: not calculated NA: not applied

  Several additional assumptions were proposed to further investigate the cause of sublingual bioavailability measured above 100%. These assumptions include the analytical interaction of propofol (used as an anesthetic in the sublingual route) and cyclobenzaprine, the binding of cyclobenzaprine to the device used for administration, and propofol and cyclobenza in the liver In vivo enzymatic competition of purine was included.

イヌ４は嚥下しよだれを垂らした To address the hypothesis that there is an in vivo enzymatic competition between propofol and cyclobenzaprine in the liver, four dogs were treated with or without propofol either under the tongue or IV as follows . One dog is treated with IV without propofol pre-anesthesia, one dog is pre-anesthetized with propofol and treated with IV, and one dog is treated sublingually without propofol prior to anesthesia One dog was pre-anesthetized with propofol and treated sublingually. Each dog was sampled before and after propofol before dosing (if possible) and at 5, 10 and 20 minutes after dosing. Figures 4 and 5 show mean cyclobenzaprine concentration time profiles after IV and sublingual administration of cyclobenzaprine HCl, respectively, as compared to the main study described above. Table 57 shows dog plasma pharmacokinetic parameters. The calculated bioavailability under the same conditions is about 200%. The concentrations obtained in dogs pretreated with or without propofol are similar. Thus, hepatic enzymatic competition does not appear to be responsible for high bioavailability. Dog 4 (treated by the sublingual route without propofol) had a slightly lower concentration than dog 3 (administered with propofol), but this difference was due to the animals having swallowed and dropped It can be explained.
Table 57: Plasma pharmacokinetic parameters of dogs treated or not treated with propofol

Dog 4 swallowed swallowing

In order to address the assumption that cyclobenzaprine was attached to the device used for administration, binding studies were performed using formulations containing or not containing cyclobenzaprine. The results are shown in Table 58. The table shows that the binding of cyclobenzaprine to the dosing device was about 5% for sublingual material and 10% for intravenous material. Thus, the assumption of binding does not explain bioavailability.
Table 58: Results of binding tests

To determine if propofol can interfere with the analysis of cyclobenzaprine in either pure solution or plasma, combine propofol and cyclobenzaprine in vitro to determine if the measurement of cyclobenzaprine was affected Conducted research to determine the The test results are shown in Table 59. Before and after propofol before dosing, it is below the quantification level (ie below 0.1 ng / mL), there is no interference in the chromatographic peak and there is no analytical contribution of propofol as observed. Thus, there appears to be no interaction between propofol and cyclobenzaprine.
Table 59: Analysis of propofol contribution to cyclobenzaprine

Based on previous studies, our initial assumption that the phenomenon of bioavailability may be explained by the delay between administration and blood sampling (which may differ slightly in the intravenous and sublingual routes) , Seems to be the most likely. This delay may result in metabolism over time after intravenous administration rather than the sublingual route. Nevertheless, we conclude that the bioavailability of cyclobenzaprine administered sublingually to beagle dogs is very high, likely to be close to 100%.
(Example 10)

Control tablet without basifying agent and basifying agent (K ₂ HPO ₄ ) to study the level of cyclobenzaprine plasma concentration after single sublingual administration of cyclobenzaprine HCl in female beagle dogs Two sublingual tablet formulations of the containing tablet were compared. Next, pharmacokinetic parameters were calculated and compared.

Each dog is given a sublingual cyclobenzaprine tablet first with a formulation containing a basifying agent, followed by a formulation without a basifying agent, with a 2-week washout period between each dose did. For sublingual administration, dogs were given propofol and placed in the side down position (ventral crest). The mouth was gently opened and the tablet was placed under the tongue. Then immediately returned the tongue to its initial position and closed the mouth. The dog was left in the same position until waking up. Dogs treated with cyclobenzaprine with a formulation containing a basifying agent (K ₂ HPO ₄ ) were sedated with 6.5 mg / kg propofol intravenously. Next, a single sublingual tablet, equivalent to 2.4 mg of cyclobenzaprine HCl, was administered (ie, one tablet per dog). After a two week washout period, the dogs were similarly rested and a single dose sublingual formulation without basifying agent was administered. Blood samples after both types of treatment were taken pre-dose and at 5, 10, 20, 30 and 45 minutes and at 1, 2, 3, 4, 6, 8 and 10 hours after administration. Blood was collected from the jugular vein. In all cases, animals were not given water for 30 minutes after dosing.

  The cyclobenzaprine analysis was performed according to the aforementioned analysis method. This method involved liquid-liquid extraction with hexane. The extract was injected using an “Onyx monolithic Phenomenex C18 100 × 3.0 mm” column, using an HPLC system and an API 4000® for MS / MS detection (Applied Biosystems). This method was linear from 0.1 ng / mL to 50 ng / mL for cyclobenzaprine in dog plasma. Quality control samples were prepared at 0.3, 25 and 40 ng / mL for cyclobenzaprine in dog plasma. The results obtained from the analysis of quality control samples were within the tolerance limits defined in the protocol, thus confirming the measured concentrations in plasma samples.

表６１：Ｋ_２ＨＰＯ_４を伴う個体のシクロベンザプリン血漿濃度

ＢＬＱ：定量限界（０．１ｎｇ／ｍＬ）未満
ＢＬＱ：定量限界（１ｎｇ／ｍＬ）未満（プロトコルに従って血漿試料を希釈した）
ＮＡ：適用されず
表６２：Ｋ_２ＨＰＯ_４を伴わない個体のシクロベンザプリン血漿濃度

ＢＬＱ：定量限界（０．１ｎｇ／ｍＬ）未満
ＢＬＱ：定量限界（１ｎｇ／ｍＬ）未満（プロトコルに従って血漿試料を希釈した）
ＮＡ：適用されず
表６３：薬物動態パラメータ、個々のビーグル犬

表６４：相対的バイオアベイラビリティ、個々のビーグル犬

（実施例１１） Sublingual administration was performed by anaesthetizing the female beagle slightly with propofol and placing a control tablet or a tablet containing K ₂ HPO ₄ under the tongue. The results obtained, K cyclobenzaprine tablets containing ₂ HPO ₄ is that the bioavailability than cyclobenzaprine when administered in a tablet containing no K ₂ HPO ₄ is believed to about 25% higher Shown (Figures 6 and 7; Tables 60-64). In addition, 0-7. 5 hours with beagle treated with cyclobenzaprine with K ₂ HPO ₄ (AUC = 135.6 ng · hr / mL) and control cyclobenzaprine (AUC = 82.4 ng · hr / mL) The calculated AUC values are quite different. Therefore, pharmacokinetic parameters associated with cyclobenzaprine sublingual formulation is believed to be improved by adding a basic agent such as K ₂ HPO _4.
Table 60: Mean ± SD plasma PK parameters

Table 61: Cyclobenzaprine plasma concentrations of individuals with K ₂ HPO ₄

BLQ: less than the limit of quantification (0.1 ng / mL) BLQ: less than the limit of quantification (1 ng / mL) (diluted plasma sample according to the protocol)
NA: Not applicable Table 62: Cyclobenzaprine plasma concentrations of individuals without K ₂ HPO ₄

BLQ: less than the limit of quantification (0.1 ng / mL) BLQ: less than the limit of quantification (1 ng / mL) (diluted plasma sample according to the protocol)
NA: Not applicable Table 63: Pharmacokinetic parameters, individual beagle dogs

Table 64: Relative bioavailability, individual beagle dogs

(Example 11)

In order to investigate whether sublingual cyclobenzaprine is efficiently absorbed in humans, a pH 7.0-7.4 containing K ₂ HPO ₄ instead of a sublingual tablet into which a disintegration factor may be introduced A solution (2.4 mg / mL) for sublingual administration containing 2.4 mg cyclobenzaprine HCl formulation in aqueous solution can be used. Sublingual administration of cyclobenzaprine in the context of the present invention can be performed, inter alia, via sublingual tablets or liquid solutions. As mentioned above, with sublingual formulations, cyclobenzaprine is expected to have higher bioavailability and a higher degree of predictable absorption than oral tablets such as currently available tablets. As a result, the patient is less likely to take too little drug to have a therapeutic effect, is less likely to take an overdose, and has no side effects, ie, no sleepiness and / or intolerance the next day. It is possible to reduce the possibility of resulting default. Sublingual administration is also predicted to avoid the initial pass liver metabolism leading to demethylation of cyclobenzaprine to norcyclobenzaprine, among other metabolites.

  The extent to which the pH of the sublingual oral solution affects the rate or efficiency of sublingual absorption is not completely understood. The results described in Example 9 were found to be absorbed rapidly at pH 7.4. In order to more fully characterize the extent to which absorption is affected by the pH of the oral solution formulation, a sublingual solution of 2.4 mg of the cyclobenzaprine HCl formulation at pH 7.4 and pH 3.5 was tested. In order to establish a baseline of absolute bioavailability, 2.4 mg of cyclobenzaprine was also administered as an IV solution at pH 7.4 (0.6 mg / mL).

A single-center randomized, open-label, single-dose comparison, parallel-design pharmacokinetic study, designed as follows: Sublingual solution of 2.4 mg of cyclobenzaprine HCl at pH 7.4 Sublingual solution (2.4 mg / mL) of (2.4 mg / mL) and 2.4 mg of cyclobenzaprine HCl preparation at pH 3.5, oral cyclobenzaprine 5 mg immediate release tablet, and contains K ₂ HPO ₄ The rates of absorption and degree of absorption of a 2.4 mg dose of intravenous cyclobenzaprine (0.6 mg / mL) in an aqueous solution of pH 7.4 were compared. We also evaluated the safety and tolerability of a sublingual solution of 2.4 mg of a cyclobenzaprine HCl formulation at pH 3.5 and 7.4, using a tablet of cyclobenzaprine 5 mg and an intravenous solution of cyclobenzaprine 2.4 mg. Compared to safety and tolerability.

  Potentially possible subjects were screened by medical and psychiatric medical history, and laboratory and physical examination 2-30 days prior to dosing. Baseline assessments will be performed and subjects will be randomly assigned to formulation / treatment one day prior to drug administration (day -1). The next morning, after all pre-dose evaluations were completed, if eligible subjects agreed to continue, subjects were randomly assigned to study the drug, and subjects received the assigned dose of study or reference drug. Subjects had to fast for at least 10 hours prior to dosing and 4 hours after dosing.

  Subjects were detained at least 10 hours prior to dosing until the 72-hour discharge procedure was complete. Subjects remained in sitting or semi-reclining for up to 4 hours after administering the assigned study drug unless medically required or procedurally required, and it was necessary to avoid lying or sleeping. Because of the long restraint time, supervised outings were permitted during the restraint period. Going out was not permitted on the day of administration (day 1).

  Tests for thyroid stimulating hormone (TSH), human immunodeficiency virus types 1 and 2 (HIV1 and HIV2), hepatitis B (HBsAg), and hepatitis C (HCAb) were performed only at screening, and drug screening in urine, alcohol The breath test and the urinary cotinine test were performed at screening and admission. Physical examination, laboratory tests, vital signs, 12-lead electrocardiogram (ECG), body weight / body mass index (BMI), and pregnancy tests were performed at specific intervals. Monitoring of adverse events (AEs) and concomitant medications was ongoing. Blood and urine samples were collected at specific intervals to measure cyclobenzaprine and norcyclobenzaprine levels in plasma and urine. A post-study follow-up call was scheduled 10 ± 3 days after administration of the assigned study medication. For subjects suspended prematurely, every effort was made to complete a discharge assessment and follow-up call.

And K ₂ sublingual cyclobenzaprine HCl solution in an aqueous solution of pH3.5 containing _{HPO 4 2.4mg (2.4mg / mL)} , sublingual cycloalkyl in the aqueous solution of pH7.4 containing K 2 HPO ₄ The purpose of comparing the absorption rates and absorbencies of benzaprine HCl solution 2.4 mg (2.4 mg / mL) was to analyze the absorption rates associated with the two formulations via analysis of multiple plasma and urine samples collected from the subject And by comparing the degree of absorption. Sublingual cyclobenzaprine HCl solution at pH 3.5 and pH 7.4 and 2.4 mg (2.4 mg / mL) of oral cyclobenzaprine 5 mg tablets and intravenous cyclobenza in an aqueous solution containing K ₂ HPO ₄ The purpose of comparing absorption rates and absorbencies of purine 2.4 mg (0.6 mg / mL) (reference formulation) relates to these formulations or treatments via analysis of multiple plasma and urine samples collected from the subject Achieved by comparing the rate of absorption and the degree of absorption. The purpose of evaluating the safety and tolerability of a sublingual solution formulation (2.4 mg / mL) of cyclobenzaprine HCl 2.4 mg at pH 3.5 and 7.4 was to be used before, during and during the 4-day hospitalization period. At the end, work was done by monitoring AE, laboratory values, vital signs, 12-lead ECG, body weight / BMI, concomitant medications, and overall health.

Each potential subject presented signed informed consent prior to performing the screening procedures associated with any of the studies. The researchers interviewed the subject and performed a per-protocol screening assessment to determine the subject's potential relevance to the study. Subjects were administered a single dose treatment according to the block randomization scheme. For a total of 24 enrolled subjects, 6 subjects were randomly assigned to each of the 4 groups.
The four treatments were as follows.
Treatment A: One dose of 2.4 mg of cyclobenzaprine HCl sublingual solution (2.4 mg / mL) in an aqueous solution of pH 3.5 containing K ₂ HPO ₄ is administered as 1 mL for 90 seconds without swallowing It was kept under the tongue.
Treatment B: A dose of 2.4 mg of cyclobenzaprine HCl sublingual solution (2.4 mg / mL) is administered as 1 mL in an aqueous solution of pH 7.4 containing K ₂ HPO ₄ for 90 seconds without swallowing It was kept under the tongue.
Treatment C: A dose of 5 mg of cyclobenzaprine immediate release tablet was swallowed with 240 mL of water at room temperature.
Treatment D: One dose of 2.4 mg of cyclobenzaprine USP (0.6 mg / mL) in an aqueous solution of pH 7.4 containing K ₂ HPO ₄ was intravenously administered over 30 seconds as a 4 mL bolus injection.

  Each subject participated for up to approximately 43 days, including a screening period of up to 30 days, a hospitalization dosing period of 4 days, and a follow-up call 10 ± 3 days after study drug administration.

A low dose of cyclobenzaprine HCl sublingual solution 2.4 mg (2.4 mg / mL) was administered sublingually via a Becton Dickinson 1 mL needle-free syringe. The sublingual solution consisted of cyclobenzaprine USP dissolved in an aqueous solution containing K ₂ HPO ₄ at a concentration of 2.4 mg / mL. The solution was prepared as two identical formulations except that one was provided at pH 7.4 and the other at pH 3.5. Two subbenzal preparations of cyclobenzaprine HCl 2.4 mg were filled into single use 3 mL vials (1.5 mL per 3 mL vial), labeled, packaged, and prepared for use in the study.

  Cyclobenzaprine intravenous solution containing 0.6 mg / mL cyclobenzaprine USP was used as a reference comparison in this trial. This solution was identical to the sublingual solution of 2.4 mg cyclobenzaprine HCl, except that it was formulated to a concentration of 0.6 mg / mL, and the pH was adjusted to 7.4. This cyclobenzaprine 2.4 mg intravenous solution was filled into single use sterile 10 mL vials (5 mL per 10 mL vial), labeled, packaged, and prepared for use in the study.

  Blood and urine samples for pharmacokinetic analysis were collected and vital signs were recorded at specific intervals before and after dosing. Laboratory tests and 12-lead ECGs were performed before discharge on the morning of day -1 and day 4. Serum β-HCG pregnancy tests were performed on all women subjects on day -1. The urine β-HCG pregnancy test was performed on all female subjects prior to discharge on the morning of the fourth day. Monitoring of adverse events and concomitant medications was conducted continuously.

  For pharmacokinetic analysis, within 30 minutes prior to administration, and 5, 10, 20, 30 and 45 minutes after administration, and 1, 2, 2.5, 3, 3.33, 3.67, 4, 4. A total of 25 blood samples (6 mL per sample) are taken after 33, 4.67, 5, 5.5, 6, 8, 12, 16, 24, 36, 48 and 72 hours. The actual sampling time was used for statistical analysis. Where blood collection and other procedures co-occurred, blood collection was preceded, unless otherwise specified, or for the safety of the subject. Where appropriate, dead volume intravenous catheters were used for blood collection to avoid multiple skin punctures. Otherwise, blood samples were collected by direct venipuncture. Tables for evaluation once daily and hourly are shown in FIGS. 8 and 9, respectively.

In pharmacokinetic analysis, a single urine sample is collected within 30 minutes before administration (one sample), and then administered 0-24 hours, 24-48 hours and 48-72 hours after administration The urine was collected for a period. If the subject failed to urinate within 30 minutes prior to dosing, then the previous morning sample could be used as a pre-dose sample. The urine that the subject urinated within 10 minutes before the end of the interval was included in the previous samples. Subjects were asked to urinate within 5 minutes before the end of each collection interval, so each new interval could start with the bladder empty. Any urine that the subject urinated but was not collected was recorded. The pharmacokinetic parameters (plasma) _{is, AUC 0-t, AUC 0} -inf, C max, the residual area _{(Residual area), T max,} T 1 / 2el, were included _{K el,} and F. F was calculated for sublingual and oral formulations of cyclobenzaprine only. Pharmacokinetic parameters (urine) included Aeo _-t , _Rmax , and _Tmax .

For blood samples, ANOVA _were carried out in T _{max, K el} and _{T 1 / 2el,} and _{AUC 0-t,} alpha level 0.05 _{AUC 0-inf} and _{C max.} 90% geometric confidence of the ratio of the means (treatment A / B, A / C, A / D, B / C and B / D) and the ratio of the averages based on the least squares means obtained from the ANOVA of the ln transformation data Intervals (CI) were calculated for _{AUCo -t} , AUCo _-inf and _Cmax . For all analytes, the ratio of the means (treatment A / B, A / C, A / D, B / C and B / D) and the ratio of the means based on the least squares means obtained from the ANOVA of ln conversion data 90% geometric CI was calculated for Ae _{0 -t} and R _max .

  Discharge from the study ward took place after the planned discharge assessment (morning 4th day) was completed 72 ± 1.5 hours after study drug administration. In the absence of safety concerns, subjects were discharged from the research ward after these visits (ie, four days after dosing) at the discretion of the investigator.

  Three to nine days after discharge from the research ward (ie, 10 ± 3 days after administration), the research staff made a follow-up call to each subject. Subjects were asked to report any adverse events that have been experienced since discharge from the research ward. Subjects were considered to have completed the study after receiving a follow-up call.

^ａｐＨ７．１の２．４ｍｇ舌下溶液の平均から、対象７（外れ値）および舌下溶液医薬品を嚥下したと思われる対象１０は排除された。
^ｂｐＨ３．５の２．４ｍｇ舌下溶液の平均から、舌下溶液医薬品を嚥下したと思われる対象４は排除された。
^ｃ各対象は、単一のシクロベンザプリン５ｍｇ経口錠剤を投与された。 This experiment is designed to be a rigorous test for transmucosal absorption after sublingual administration of oral cyclobenzaprine solution, so the subject holds the solution sublingually for 90 seconds and the contents in the mouth Exhaled, rinse mouth with 60 mL water, then instructed to drink 240 mL water. Although different from beagles under anesthesia, some of the alert humans were expected to swallow some of the sublingual solution as part of their involuntary reflexes. Table 65 shows the study results.
Table 65: Mean plasma cyclobenzaprine pharmacokinetics

^a . Subject 7 (outliers) and subject 10 that appeared to have swallowed the sublingual solution were excluded from the average of the 2.4 mg sublingual solution at pH 7.1.
^b Subject 4 who appeared to have swallowed the sublingual solution drug was excluded from the average of 2.4 mg sublingual solution of pH 3.5.
^c Each subject received a single cyclobenzaprine 5 mg oral tablet.

  As expected, several subjects swallowed the sublingual dose. Subject 7 was excluded from the analysis summarized in Table 65, as the sublingual dose absorption was much more rapid than the absorption of other humans who received one of the sublingual treatments, but It seems most likely to be the most complete adherence to the intended dosing procedure and the most straightforward representation of the potential of sublingual administration. Data analysis showed that the subject 7 of the cohort receiving 2.4 mg sublingual solution at pH 7.1 was significantly similar to the average of all cohorts receiving 2.4 mg IV solution over the 0-1 hour time frame. The cohort receiving the cyclobenzaprine 5 mg tablet showed little absorption within this time period. The absorption efficiency of subject 7 was approximately half that of the cohort receiving the 2.4 mg IV solution. The concentration-time profiles of subject 7 in the cohort receiving 2.4 mg IV solution and the cohort receiving 2.4 mg sublingual solution at pH 7.1 have two distinctly different phases in the first hour The first phase shows a rapid rise in clearance from plasma within 5 minutes (0.83 hours), the second phase 10 minutes (0.167 hours) to 60 minutes (1 hour) Relatively flat plasma concentrations. Since the plasma levels of oral administration shown in Figure 10 were reduced by 2.4 / 5.0 times, the data of the 2.4 mg sublingual (SL) solution could easily be compared with the data of the cyclobenzaprine 5 mg oral (PO) tablet group It was possible to assume dose proportionality in comparison with. During the first hour, plasma samples are taken at 0 minutes, 2 minutes (0.033 hours), 3 minutes (0.058 hours), 5 minutes (0.083 hours), 10 minutes (0.167 hours), Obtained at 20 minutes (0.33 hours), 30 minutes (0.5 hours), 45 minutes (0.75 hours) and 60 minutes (1 hour) (FIG. 10).

A preliminary analysis of pharmacokinetic data over 24 hours showed that subject 7 of the cohort receiving 2.4 mg SL solution at pH 7.1 was similar to the concentration-time profile over 24 hours of the entire cohort receiving 2.4 mg IV solution. I showed that I continued to show the profile. Also, analysis of pharmacokinetic data over 24 hours showed that plasma levels in the cohort receiving 2.4 mg IV solution dropped rapidly in 1 to 5 hours, and those in the cohort receiving cyclobenzaprine 5 mg tablets It showed that it increased to T _max at about 5 hours. Plasma levels in the cohort receiving 2.4 mg IV solution showed a slight increase after 5 hours, which indicates that some of the initial dose enters the bile and then portal circulation (enterohepatic recirculation) It is consistent with being taken in. As the indicated plasma levels of oral administration dropped by 2.4 / 5.0 times, the data of 2.4 mg SL solution is easily compared with the data of cyclobenzaprine 5 mg oral tablet group and assuming dose proportionality I could do it (Figure 11).

  Since Subject 7 is an outlier, we used 4 other subjects in the cohort who received 2.4 mg SL solution at pH 7.1 and subjects who received 2.4 mg SL solution at pH 3.5, The mean pharmacokinetics of subjects who received and cyclobenzaprine 5 mg oral tablets were also compared. The group receiving 2.4 mg SL solution at pH 7.1 showed a rapid rise in plasma cyclobenzaprine over the first hour (FIG. 12). In contrast, very low levels of cyclobenzaprine were observed over this time period in either the cohort receiving 2.4 mg SL solution at pH 3.5 or the cohort of cyclobenzaprine 5 mg oral tablets. From the group mean of the 2.4 mg SL solution at pH 7.1, subject 7 (outliers) and 10 (which seemed to have swallowed the SL solution drug) were excluded, and from the group mean of the 2.4 mg SL solution at pH 3.5 , Subject 4 (which appeared to have swallowed the SL solution drug) is excluded. The plasma levels shown for the cyclobenzaprine 5 mg oral tablet were reduced by 2.4 / 5.0 times, so the data from the 2.4 mg SL solution group were easily compared with the data for the cyclobenzaprine 5 mg oral tablet group, and the dose Proportionality could be assumed. These findings indicated that phosphate in 2.4 mg SL solution at pH 7.1 was associated with increased transmucosal absorption of cyclobenzaprine after sublingual administration.

  To determine whether sublingual administration of 2.4 mg SL solution (cyclobenzaprine HCl) has an effect on the formation of the long-lived metabolite norcyclobenzaprine, determine the plasma levels of this metabolite did. As shown in FIG. 13, norcyclobenzaprine levels in the IV cohort and subject 7 tended to be lower than the group mean observed in the cohort of cyclobenzaprine 5 mg oral tablets, which may be sublingual or It is consistent with the reduction of first pass metabolism by IV administration.

  The 2.4 mg SL solution at pH 7.1 had a benign safety profile. Adverse events (TEAEs) that appeared with all treatments in this cohort were mild, and all but one (with increased lipase) had recovered by the time the laboratory was discharged (elevated lipase , Detected in samples obtained at the time of discharge, and subjects failed to follow up). The TEAEs of all four cohorts were mild or moderate and were generally compatible with the labeling of commercial cyclobenzaprine tablets.

（実施例１２） Additional pharmacokinetic analysis of the data was performed on each individual subject by calculating the partial AUC for up to 8 hours from time 0 to each sampling time. Group A partial AUC data were then dose normalized to the same dose as group B (5 mg to 2.4 mg) to assume linear pharmacokinetics. Geometric means were calculated for the partial AUCs of the two groups. The geometric mean is preferably compared to the arithmetic mean due to the normal log-average distribution of pharmacokinetic parameters such as AUC. Finally, partial AUCs were statistically compared among the groups. Along with the use of geometric mean, t-test of unpaired samples was performed after log-transforming partial AUC. The results are AUC (0-0.5 hours), AUC (0-0.75 hours), AUC (0-1 hours), AUC (0-2 hours) and AUC (0-2.5 hours), It was shown to be significantly higher after administration of the solution containing phosphate compared to tablets (Table 66). This means that at any time during the first 2.5 hours after administration, a solution containing phosphate achieved higher systemic exposure than compared to tablets.
Table 66: Partial AUCs of Groups B and C

(Example 12)

  A single dose, open label, randomized, parallel design study of comparative pharmacokinetics and safety of sublingual cyclobenzaprine tablets was conducted. The study compared doses of 2.4 mg and 4.8 mg sublingual cyclobenzaprine tablets (including phosphate), 2.4 mg sublingual cyclobenzaprine tablets (without phosphate), and cyclobenzaprine 5 mg oral tablets did. The study included: 1) Absorption rate and degree of absorption of 2.4 mg sublingual cyclobenzaprine HCl tablets with and without phosphate, and 2) 2.4 mg sublingual cyclobenza administered at doses 2.4 mg and 4.8 mg Compare the absorption rate and degree of absorption of Purine HCl tablet (with phosphate) and 2.4 mg sublingual cyclobenzaprine HCl tablet (without phosphate) with cyclobenzaprine 5 mg oral tablet, and 3) 2.4 mg and 4.8 mg doses of sublingual cyclobenzaprine HCl tablets (including phosphate) and 2.4 mg doses of 2.4 mg sublingual cyclobenzaprine HCl tablets (without phosphate) Assess the safety and tolerability of cyclobenzaprine 5 mg oral tablets.

Patients were selected substantially as described in Example 11. Cyclobenzaprine was administered as follows.
Treatment A: Single dose of one TNX-102 2.4 mg SL tablet (including phosphate). Subjects were asked to hold the tablet under the tongue until the tablet was dissolved and not to crush or chew. Subjects were asked not to drink at all until at least one hour after dosing.
Treatment B: Single dose of one TNX-102-A 2.4 mg SL tablet (without phosphate). Subjects were asked to hold the tablet under the tongue until the tablet was dissolved and not to crush or chew. Subjects were asked not to drink at all until at least one hour after dosing.
Treatment C: Single dose of two TNX-102 2.4 mg SL tablets (including phosphate). The subject was asked to hold the tablet under the tongue until the two tablets dissolved and not crush or chew. Subjects were asked not to drink at all until at least one hour after dosing. Treatment D: Single dose of one cyclobenzaprine 5 mg oral immediate release tablet (Watson Pharmaceuticals) swallowed with 240 mL water at room temperature. The subject was asked to swallow the whole administered tablet and not to grind or chew it.

  Sublingual cyclobenzaprine HCl tablets were well tolerated and did not have serious adverse effects, although some subjects experienced tongue numbness. Compared to 5 mg oral cyclobenzaprine, 4.8 mg sublingual cyclobenzaprine HCl had a marked increase in the rate of absorption during the first two hours of dosing (Figures 14 and 15). In fact, at some time, sublingual cyclobenzaprine resulted in dose-adjusted mean plasma levels of cyclobenzaprine that are approximately 20 times higher compared to oral administration. Also, sublingually administered cyclobenzaprine resulted in higher AUC than orally administered cyclobenzaprine. Sublingual cyclobenzaprine HCl also produced similar dose proportionality between doses 2.4 mg and 4.8 mg (Figure 16). Furthermore, sublingual tablets containing phosphate tended to absorb cyclobenzaprine faster than tablets without phosphate (FIG. 17). Table 67 shows the statistical significance of partial AUC analysis using one-way ANOVA test and Bonferroni one-way comparison between different treatment groups.

Partial AUC at different time points was calculated to investigate the effect of sublingual administration on absorption. Statistical comparisons of ln-transformed AUC data were analyzed by one-way ANOVA and Bonferroni one-way comparison (95% confidence level). Comparing the partial AUC of cyclobenzaprine HCl SL 2.4 mg (one tablet) with the AUC of cyclobenzaprine 5 mg IR tablet (dose normalized to 2.4 mg), by administration of one SL 2.4 mg tablet: It was revealed that the absorption was statistically significantly increased relative to cyclobenzaprine 5 mg IR: AUC _{0-20 min} , 37 ng hr L ^-1 vs 0 ng hr L ^-1 , p <0.05; ^{_{AUC 0-30min, 128ng · hr · L}} -1 vs. _{^{1ng · hr · L -1, p}} <0.05; AUC 0-45min, 333ng · hr · L -1 vs. ^{2ng · hr · L -1, p} <_{0.05; AUC 0-1h, 614ng · hr} · L -1 versus _{^{5ng · hr · L -1, p}} <0.05; AUC 0-2h, 2098ng · hr · L -1 pair _{^{86ng · hr · L -1, p}} <0.05; AUC 0-2.5h, 2955ng · hr · L -1 vs. _{^{791ng · hr · L -1, p}} <0.05; AUC 0-3h, 3931ng · hr · L ⁻¹ vs 1355 ng · hr · L ⁻¹ , p <0.05.

（実施例１３） Partial AUC at different time points was analyzed to show the effect of SL administration of cyclobenzaprine HCl on absorption. Statistically significant absorption when comparing the average partial AUC of two tablets of 2.4 mg cyclobenzaprine HCl with the average partial AUC of an IR tablet of cyclobenzaprine 5 mg (dose normalized to 2.4 mg) An increase in AUC _{0-20 min} was found: AUC _{0-20 min} , 23 ng hr L- ¹ vs 0 ng hr L- ¹ , p <0.05; AUC _0-30 min 86 ng hr L- ¹ vs 1 ng. _{^{hr · L -1, p <0.05}} ; AUC 0-45min, 223ng · hr · L -1 vs. _{^{2ng · hr · L -1, p}} <0.05; AUC 0-1h, 405ng · hr · L - ¹ vs. 5 ng · hr · L ⁻¹ , p <0.05; AUC _{0-2 h} , 1478 ng · hr · L ⁻¹ vs. 386 ng · hr · L ⁻¹ , p <0.05; AUC _{0-2.5 h} 2167 ng hr · ^{L -1} vs. ^{791ng · hr · L -1, p} <0.05.
Table 67: One-way ANOVA vs Bonferroni One-way Comparison (95% confidence level)

(Example 13)

  Although cyclobenzaprine has been shown to interact with both serotonergic and noradrenergic receptor systems, the functional interaction of cyclobenzaprine with the isolated receptor is fully characterized It is not known about norcyclobenzaprine. Thus, plasma norcyclobenzaprine may be measured in healthy subjects after oral administration of cyclobenzaprine and the binding and functional activity of cyclobenzaprine and norcyclobenzaprine may potentially be related to cyclobenzaprine action We studied on a set of sex-targeted CNS targets.

表６９：中枢神経系に発現する標的に対するシクロベンザプリンおよびノルシクロベンザプリンの結合および機能的効力

ＩＰ：イノシトール三リン酸；ｃＡＭＰ：３’−５’−アデノシン一リン酸；ＴＰ：輸送体；ＮＡ：活性なし；ＮＤ：行われず Cyclobenzaprine and norcyclobenzaprine were screened with a broad panel of receptors, channels, enzymes and transporters. Balanced receptor binding assays were performed on selected recombinant human serotonin, adrenergic, histamine, and cell lines expressing muscarinic receptors. Selected receptors were also analyzed for functional antagonism in ligand-induced intracellular calcium mobilization and β-arrestin signaling. Figures 18a-h show equilibrium binding of cyclobenzaprine (circles) and norcyclobenzaprine (triangles) to cells expressing various recombinant human receptors. In particular, FIG. 18 b shows that 5-HT _2A receptors bind with a K _i of approximately 10 ^−6.8 to 10 ^−8.8 , which indicates that cyclobenza in the blood or central nervous system Despite the baseline level of purine, it may be consistent with the dynamic effects of bedtime dosing on the central nervous system. Table 68 also shows the ratio of Hill plots (also called Hill gradients or gradient factors) showing the slopes of the curves of the receptors of Figures 18a-h. A slope ratio less than one indicates a wide dynamic range, and a slope ratio greater than one indicates a narrow dynamic range. Narrow dynamic range means that when the cyclobenzaprine concentration is increased over a narrow concentration range of cyclobenzaprine, the receptor (eg, H-1 receptor) population shifts from unoccupied to occupied . Similarly, when the cyclobenzaprine concentration decreases, the receptor population shifts from occupied to unoccupied. A broad dynamic range means that when the cyclobenzaprine concentration is increased over a wide concentration range of cyclobenzaprine, the receptor (eg, 5HT2A receptor) population shifts from unoccupied to occupied. Similarly, when the cyclobenzaprine concentration decreases, the receptor shifts from occupied to unoccupied. Since K _i is the inflection point of the curve (50:50 bound: non-bound), at a concentration of 10 times that of K _i , the “narrow dynamic range” receptor has Henderson-Hasselbach-like features It can be predicted to have a receptor that is 95: 5 bound: unbound and can be predicted to be in a range beyond the linear range where more ligand can bind to a diminishing amount of receptor. However, in the "broad range of dynamic range" receptors, it is possible to predict that the receptor binds less than 95% and is within the linear range where more ligand can bind to more receptors. These considerations are important as the K _i values of the 5HT2A and H-1 receptors are close to the therapeutic levels of cyclobenzaprine which results in 2.75 ng / ml cyclobenzaprine (10 nM) in plasma. Therapeutically, administration of cyclobenzaprine at bedtime should alter occupancy of the 5HT2A receptor and the H-1 receptor, but the 5HT2A receptor has a greater dynamic range and thus a higher degree of Should be affected. FIG. 19 shows similar binding studies of transporters expressed in the central nervous system. Table 69 shows the binding affinity and functional potency of cyclobenzaprine and norcyclobenzaprine for various central nervous system proteins.
Table 68: Hill plot ratio (or Hill slope)

Table 69: Binding and functional efficacy of cyclobenzaprine and norcyclobenzaprine for targets expressed in the central nervous system

IP: inositol triphosphate; cAMP: 3'-5'-adenosine monophosphate; TP: transporter; NA: no activity; ND: not performed

表７１：４つのパラメータによるＨｉｌｌ勾配（またはフィット勾配）の比；β−アレスチンシグナリング

（実施例１４） After conducting the aforementioned binding studies, functional studies of cyclobenzaprine and norcyclobenzaprine on central nervous system receptors were conducted. In these assays, G protein-dependent signaling by intracellular Ca ²⁺ mobilization, cAMP production or turnover of inositol triphosphate (Figure 20a-h, Table 70) and G protein-independent signaling by β-arrestin signaling Both transmissions (Figure 21 ad, Table 71) were tested. Cyclobenzaprine and norcyclobenzaprine exhibited high affinity binding (K _i ) to the following receptors: 5-HT _2A (K _i = 5.2 and 13 nM, respectively), 5-HT _2B (15 and 12 nM), and _5-HT 2C (43 and 43 nM), adrenergic alpha _1A (5.6 and 34nM), α _1B (9.1 and 11nM), α _2B (21 and 150 nM) and alpha _2C (25 and _48nM); H 1 (1.3 and 5.9 nM); and _M 1 (7.9 and 30 nM). Cyclobenzaprine and norcyclobenzaprine, by Ca ²⁺ mobilization, 5-HT _2A (IC ₅₀ = 230 and 140 nM), 5-HT _2B (100 and 580 nM), H ₁ (5.2 and 16 nM), α _1A (4.9 and 16 nM), M ₁ (0.71 and 8.7) and M ₂ (3.3 and 33 nM) functional antagonists. In contrast, both cyclobenzaprine and norcyclobenzaprine were functional agonists of 5-HT _1A (EC ₅₀ = 5.3 and 3.2 μM). Cyclobenzaprine and norcyclobenzaprine are 5-HT _2A (IC ₅₀ = 99 and 181 nM), H ₁ (2.7 and 6.1 nM), α _{1 B} (144 and 173 nM), and β ₁ -arrestin signaling. It was also a functional antagonist of M ₁ (81 and 266 nM).
Table 70: Ratio of Hill slope (or fit slope) by 4 parameters; Ca ²⁺ signaling

Table 71: Ratio of Hill slope (or fit slope) by 4 parameters; β-arrestin signaling

(Example 14)

  An amitriptyline preparation not containing a basifying agent (Formulation (a)) was prepared by adding 0.049 g of amitriptyline hydrochloride, 0.052 g of sodium starch glycolate, 0.399 g of spray-dried lactose, and 0.200 g of microcrystalline cellulose. Prepared by blending. The powder was then blended with 0.024 g of magnesium stearate and the whole mixture was compressed into tablets. The tablets were placed in 15 mL of water and disintegrated in less than 30 seconds. It was 4.92 when pH of the obtained slurry was measured.

  An amitriptyline formulation containing a basifying agent (Formulation (b)) was prepared by first blending 0.051 g of amitriptyline hydrochloride and 0.105 g of sodium bicarbonate. After mixing, the powder was blended with 0.052 grams of sodium starch glycolate, 0.356 grams of spray dried lactose, and 0.205 grams of microcrystalline cellulose. Finally, the powder obtained is blended with 0.025 g of magnesium stearate and the whole mixture is compressed into tablets. The tablets were placed in 15 mL of water and disintegrated in less than 30 seconds. It was 7.49 when pH of the obtained slurry was measured.

Additional studies of formulations containing a basifying agent were performed according to the above procedure. After compression, it was noted that the tablets of each formulation disintegrate in less than 30 seconds when placed in 15 mL of water. The composition of these formulations and the pH of the resulting slurry are summarized in Table 72.
Table 72: Amitriptyline formulation and pH

Claims (1)

An article, method or system as described in the present specification and drawings.

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